JCF-01200; No of Pages 8
Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Skeletal muscle contractility and fatigability in adults with cystic fibrosis Mathieu Gruet a,b,c,⁎,1 , Nicolas Decorte a,b,1 , Laurent Mely c,d , Jean-Marc Vallier c , Boubou Camara e , Sébastien Quetant e , Bernard Wuyam a,b,2 , Samuel Verges a,b,2 a
e
Grenoble-Alpes University, HP2 Laboratory, 38000 Grenoble, France b INSERM, U1042, 38000 Grenoble, France c LAMHESS EA 6312, Universities of Toulon and Nice Sophia-Antipolis, France d Regional Cystic Fibrosis Unit (CRCM), Renée Sabran Hospital, Giens, France Regional Cystic Fibrosis Unit (CRCM), Thoracic and Vascular Department, Grenoble University Hospital, France Received 19 February 2015; revised 12 May 2015; accepted 13 May 2015
Abstract Background: Recent discovery of cystic fibrosis transmembrane conductance regulator expression in human skeletal muscle suggests that CF patients may have intrinsic skeletal muscle abnormalities potentially leading to functional impairments. The aim of the present study was to determine whether CF patients with mild to moderate lung disease have altered skeletal muscle contractility and greater muscle fatigability compared to healthy controls. Methods: Thirty adults (15 CF and 15 controls) performed a quadriceps neuromuscular evaluation using single and paired femoral nerve magnetic stimulations. Electromyographic and mechanical parameters during voluntary and magnetically-evoked contractions were recorded at rest, during and after a fatiguing isometric task. Quadriceps cross-sectional area was determined by magnetic resonance imaging. Results: Some indexes of muscle contractility tended to be reduced at rest in CF compared to controls (e.g., mechanical response to doublets stimulation at 100 Hz: 74 ± 30 Nm vs 97 ± 28 Nm, P = 0.06) but all tendencies disappeared when expressed relative to quadriceps cross-sectional area (P N 0.5 for all parameters). CF and controls had similar alterations in muscle contractility with fatigue, similar endurance and post exercise recovery. Conclusions: We found similar skeletal muscle endurance and fatigability in CF adults and controls and only trends for reduced muscle strength in CF which disappeared when normalized to muscle cross-sectional area. These results indicate small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) muscle alterations in CF with mild to moderate lung disease. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Skeletal muscle function; Exercise tolerance; Neuromuscular fatigue
1. Background Exercise has many positive effects on various health outcomes in cystic fibrosis (CF) and higher levels of physical fitness are associated with better quality of life [1] and better survival in this
population [2, 3]. Although exercise intolerance is a hallmark of CF disease, the exact underlying mechanisms remain to be elucidated, in particular to optimize exercise rehabilitation programs. It is acknowledged that pulmonary factors alone are insufficient to explain exercise intolerance in CF, especially in
Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CPET, cardiopulmonary exercise test; Db10, potentiated doublets at 10 Hz; Db100, potentiated doublets at 100 Hz; Db10:100, ratio between potentiated doublets at 10 Hz and 100 Hz; FEV1, forced expiratory volume in one second; FMNS, femoral magnetic nerve stimulation; Mmax, maximal M-wave; MVC, maximal voluntary contraction; PA, physical activity; qCSA, quadriceps cross-sectional area; Twp, potentiated twitch amplitude; VA, maximal voluntary activation; VADb, maximal voluntary activation from doublets at 100 Hz; VATwp, maximal voluntary activation from potentiated twitch. ⁎ Corresponding author at: LAMHESS EA 6312, Université de Toulon, BP 20132, 83957 La Garde, France. Tel.: + 33 494142661; fax: +33 494142278. E-mail address: [email protected] (M. Gruet). 1 The first two authors contributed equally to this study. 2 The last two authors shared the senior authorship. http://dx.doi.org/10.1016/j.jcf.2015.05.004 1569-1993© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
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M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
patients with mild to moderate lung disease. For example, inhaled bronchodilators improve lung function but not maximal exercise capacity in CF [4]. Recent evidence suggests that skeletal muscle dysfunction may play an important role regarding exercise intolerance in CF. Some studies demonstrated a reduction in maximal muscle strength which was related with exercise intolerance in both children and adults with CF [5–7]. This muscle weakness has been traditionally explained by physical inactivity and altered nutritional status. However, muscle weakness observed in a large sample of CF has been found to be in excess to that expected from physical inactivity alone [6]. Moreover, 6 months of endurance and/or resistance training failed to improve muscle strength despite normal nutritional status [8], questioning CF skeletal muscle trainability. Thus, the hypothesis of specific physiological impairments in the CF skeletal muscles can be raised. Wells et al. [9] found abnormalities in muscle metabolism in CF children as compared with age, sex and habitual physical activity (PA)-matched healthy controls, suggesting intrinsic dysfunction of skeletal muscle function. Lamhonwah et al. [10] recently demonstrated that CF transmembrane conductance regulator (CFTR) is expressed at the sarcoplasmic reticulum of human skeletal muscle. It has been proposed that sarcoplasmic reticulum CFTR Cl− channels deficiency could perturb electrochemical gradient, leading to Ca2 + homeostasis dysregulation which could alter excitation– contraction coupling. These data suggest intrinsic CF-related skeletal muscle abnormalities, which may contribute to contractile impairments, increased muscle fatigability and reduced functional capacities in adults with CF. Neuromuscular function can be assessed with artificial muscle stimulation, which allows differentiation between peripheral (i.e., sarcolemmal action potentials propagation, excitation– contraction coupling, contractility) and central (i.e., spinal and/or supraspinal activation of the skeletal muscles) factors accountable for reduced strength and increased fatigability. We recently developed an isolated muscle exercise test which combines voluntary and magnetically-evoked contractions [11]. This test permits to evaluate kinetics of changes in peripheral and central mechanisms of fatigue in a large muscle group (i.e., quadriceps) and limits the influence of motivational factors using progressive loading, non-volitional contractions and multiple assessments. This test is reliable [11] and sensitive to small differences in muscle contractility and fatigability [11, 12]. We hypothesized that CF adults would have altered resting muscle contractility, even when normalized to muscle crosssectional area, and increased muscle fatigability due to exaggerated alterations in excitation–contraction coupling, as compared to age, sex and habitual PA-matched healthy controls. We also hypothesized that these neuromuscular impairments would be associated with reduced exercise tolerance. 2. Methods 2.1. Study population Fifteen adults with CF were recruited from two regional cystic fibrosis units (CRCM Grenoble and CRCM Giens). Main
subjects' characteristics are presented in Table 1. Patients were not included if they were clinically unstable; had contraindications for maximal exercise testing or severe knee condition; had severe pulmonary disease (i.e., forced expiratory volume in one second (FEV1) b 50% of predicted values); were receiving long-term oxygen therapy or corticotherapy or were physically inactive (i.e., less than 60 min of PA per week). Fifteen healthy subjects matched for age, sex and levels of PA were recruited from the hospital staff and visitors to constitute a control group. Written informed consent was obtained and the study was conducted according to the declaration of Helsinki and approved by the local Committee on Human Research (CPP Sud-Est V, Institutional Review Board number n° 1095538) (see Supplementary material for details). 2.2. Experimental design All subjects answered questionnaires, performed a cardiopulmonary exercise test (CPET) and a quadriceps evaluation (e.g., neuromuscular fatigue test and determination of quadriceps cross-sectional area, qCSA) in random order within two days. Habitual PA was measured using the Baecke questionnaire [13]. Health related quality of life was assessed by the French version of the CF questionnaire for adults (CFQ14 +) [14]. CPET was performed using an electronically braked cycle ergometer with breath by breath gas exchanges measurement (see Supplementary material). 2.3. Quadriceps cross-sectional area Subjects underwent magnetic resonance imaging assessment with a 3.0 T whole-body system (Achieva TX, Philips, Amsterdam, Netherlands) to determine qCSA (see Supplementary material). 2.4. Quadriceps neuromuscular evaluation 2.4.1. Experimental set-up All measurements were performed on the right leg under isometric conditions, as previously described [11]. Briefly, subjects laid supine in a custom-built chair with knees at 90° of flexion and the hip angle at 130°. Knee extensor force was measured during voluntary and evoked contractions by calibrated force transducer. Surface EMG signals were recorded from the right vastus lateralis (as a surrogate for the whole quadriceps) according to SENIAM recommendations. Two magnetic stimulators (Magstim 200, The Magstim Company Ltd, Whitland, UK) linked by Bistim Module (Magstim) were used to stimulate the femoral nerve, as previously described [15]. Single (1 Hz, twitch) and paired (10 Hz and 100 Hz doublets) femoral magnetic nerve stimulations (FMNS) of 1-ms duration were delivered via a figure-eight of coil at the maximum stimulator output. The coil was positioned high in the femoral triangle in regard to the femoral nerve and manually controlled by an experienced investigator throughout the protocol (see Supplementary material).
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
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Table 1 Baseline characteristics and questionnaires in CF and controls. CF (n = 15)
Controls (n = 15) 12/3 27 ± 5 22 ± 3
Pancreatic insufficiency, number (%) CF related diabetes, number (%) Glucose intolerance, number (%) Antibiotics therapy, number per year*
12/3 28 ± 6 21 ± 3 9 × ΔF508del hom, 4 × ΔF508del het, 1 × W1089x, 1 × G628R [G → A] 15 (100) 3 (20) 6 (40) 0.6 ± 1.1
Pulmonary function FEV1,L [% pred] FVC, L [% pred] FEV1/FVC,% SVC, L [% pred] TGV, L [% pred] RV, L [% pred] TLC, L [% pred]
2.8 ± 0.9 [72.0] 4.1 ± 0.9 [89.1] 68 ± 11 4.2 ± 1.0 [83.7] 4.1 ± 0.8 [134.2] 2.8 ± 0.7 [180.3] 7.0 ± 1.1 [113.2]
4.3 ± 1.4 [101.6] 5.1 ± 1.1 [102.9] 81 ± 4
2.6 ± 0.5 2.3 ± 0.4 3.2 ± 0.6
2.8 ± 0.2 2.2 ± 0.4 3.6 ± 0.8
Sex, ratio M/F Age, yr BMI, kg/m2 Genotype
Physical activity levels and HRQoL Baecke questionnaire Work index Sport index Leisure-time index CFQ questionnaire Global score (%)
P values 0.43 0.45
b 0.01 b 0.01 b 0.01
0.21 0.43 0.19
79 ± 39
Data are given as mean ± SD. BMI = body mass index; CF = cystic fibrosis; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; HRQoL = health-related quality of life; RV = residual volume; SVC = slow vital capacity; TGV = thoracic gas volume; TLC = total lung capacity; * the year preceding enrollment in the study.
2.4.2. Quadriceps fatigue protocol After quadriceps warm-up (see Supplementary material), subjects performed three maximal voluntary contractions (MVCs) 30 s apart. The initial (Pre-exercise) neuromuscular evaluation was then performed (Fig. 1). It consisted of a 5-s MVC superimposed with 100 Hz doublet and followed after 2 s by two potentiated doublets performed in the relaxed muscle at 100 Hz (Db100) and 10 Hz (Db10) delivered 4 s apart. After 15 s of rest, the subject performed a second MVC with a superimposed twitch followed after 2 s by one potentiated twitch (Twp) in the relaxed muscle. After this Pre-exercise evaluation, subjects performed the fatiguing task which consisted in sets of 10 intermittent (5-s on/ 5-s off) isometric contractions at submaximal target force levels, starting at 10% MVC for the first set and increasing by 10% MVC each set until task failure. The fatiguing task ended when the subject was unable to maintain the target force for more than 2.5 s. Five seconds after the end of each set of 10 contractions, at exhaustion and after 10 min of recovery (Post 10), neuromuscular evaluations similar to the Pre-exercise neuromuscular evaluation were performed. Real-time visual feedback of target force levels and soundtrack indicating the contraction–relaxation rhythm were provided to subjects throughout the experiment (see Supplementary material). 2.5. Data analysis The following peripheral responses to single FMNS were calculated: Twp amplitude, maximal rate of force development
and relaxation and Mmax amplitude and area. The following peripheral responses to paired FMNS were calculated: Db100, Db10 and the ratio Db10:100. All mechanical parameters were also normalized to the qCSA determined by magnetic resonance imaging. Maximal voluntary activation (VA) was calculated by twitch interpolation, from single (VATwp) and paired (VADb) FMNS (see Supplementary material for details). The following parameters were calculated from submaximal contractions: total number of contractions (i.e., the relative endurance index), mean strength and the total force-time product (i.e., the absolute endurance index) calculated over each submaximal contraction. We analyzed data from the 10-contraction sets at 10–40% MVC (i.e., set 10%, 20%, 30% and 40%) as they were completed by all subjects. Changes in voluntary and evoked quadriceps responses from the Pre-exercise neuromuscular evaluation to set 40% and to exhaustion were used as indexes of fatigability. Changes in voluntary and evoked quadriceps responses from exhaustion to post 10 were used as indexes of recovery (see Supplementary material for details). 2.6. Statistics Statistical analyses were conducted with Statistica (version 8, Tulsa, USA). Normality of distribution and homogeneity of variances of main variables were verified using Kolmogorov– Smirnov and Levene tests, respectively. Unpaired t-tests were performed to compare CF and controls for subjects' characteristics, questionnaires scores, CPET and Pre-exercise neuromuscular
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
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M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx 100 Hz 10 Hz 1 Hz Neuromuscular evaluation Task failure
100
MVC (% Pre)
(5-s ON / 5-s OFF) x 10 20 10 0 150 s Pre exercise
Fatiguing exercise Set 10%
Set 20%
Exh
Post 10
Fig. 1. Schematic illustration of the neuromuscular protocol. Pre exercise neuromuscular evaluation consisted of two maximal voluntary contractions (MVC) with femoral nerve magnetic stimulations delivered at different frequencies in both contracted and relaxed muscle. See the text for the exact timing. This neuromuscular evaluation was repeated after each fatiguing set, at exhaustion (Exh) and after 10 min of recovery (Post 10). The fatiguing task consisted of sets of 10 intermittent (5-s on/5-s off) isometric contractions at submaximal target force levels, starting at 10% MVC with increment of 10% MVC each set until exhaustion.
parameters. Changes in mechanical and EMG parameters were analyzed during fatiguing task and recovery by two-way repeated measures ANOVAs (time × group) and Tukey's post-hoc tests. Linear regressions were calculated to investigate whether any relationship existed between neuromuscular and CPET parameters. Statistical significance was set at P b 0.05. Results are given as mean ± standard deviation. 3. Results 3.1. Baseline characteristics and maximal cycling test CF patients were well matched with controls in terms of age and sex and had similar PA levels, as demonstrated by similar scores in the three scales of habitual PA (Table 1). They had similar nutritional status, as suggested by similar body mass index values (Table 1). According to the usual criteria (see Supplementary material), all controls and CF patients performed CPET to a maximal level. CF patients had reduced peak power output, peak oxygen uptake (VO2peak) and higher ventilatory limitation as suggested by higher breathing reserve index at maximum exercise (all P b 0.05; Table 2). CF patients exhibited higher levels of oxygen desaturation than controls (P = 0.01; Table 2). 3.2. Neuromuscular function Despite some slightly reduced values, CF patients had similar qCSA, MVC and peripheral responses to both single and paired FNMS than controls at baseline (Table 3). The small nonsignificant differences disappeared when expressed relative to qCSA. VATwp and VADb did not differ at baseline between the two groups (Table 3).
Total number of submaximal contractions was not different between CF and controls (52 ± 6 vs 55 ± 8, respectively, P = 0.26). However, total force-time product was significantly smaller in CF as compared to controls (15,370 ± 5925 Nm s−1 vs 21,627 ± 9089 Nm s−1, respectively, P = 0.03). This difference disappeared when expressed relative to qCSA (P = 0.18). MVC and Twp kinetics in both groups are shown in Fig. 2. Db100, Db10, Db10:100 and Mmax amplitude kinetics in both groups are shown in Fig. 3. All peripheral mechanical parameters decreased over time in both groups (time effect, all P b 0.05), without difference between groups (time × group Table 2 Maximal aerobic capacities in CF and controls. CF (n = 15) Peak power output, W VO2peak, L min−1 [% pred] VO2peak, mL min−1 kg−1 VO2peak/qCSA, mL min−1/cm2 VO2VT, L min−1 Maximal minute ventilation, L min−1 BRImax Maximal heart rate, bpm [% pred] Oxygen desaturation (%) Maximal [La−], mmol L−1 Peak rate of perceived exertion Breathlessness Muscle fatigue
186 2.3 37 34 1.6 93
± ± ± ± ± ±
Controls (n = 15)
58 296 0.7 [87.6] 3.2 10 46 9 43 0.5 2.4 21 136
± ± ± ± ± ±
71 1.0 [106] 6 8 0.6 28
P values b 0.01 b 0.01 b 0.01 b 0.01 b 0.01 b 0.01
0.98 ± 0.12 172 ± 9 [90]
0.85 ± 0.13 189 ± 7 [98]
0.01 b 0.01
2.6 ± 2.8 10.5 ± 3.0
0.5 ± 0.8 11.7 ± 2.6
0.01 0.27
88 ± 13 88 ± 15
81 ± 21 87 ± 14
0.36 0.92
Data are given as mean ± SD. BRImax = breathing reserve index at maximum exercise; CF = cystic fibrosis; qCSA = quadriceps cross-sectional area; VO2peak = peak oxygen consumption; VO2VT = oxygen consumption at the first ventilatory threshold; [La−] = blood lactate concentration.
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx Table 3 Baseline neuromuscular function in CF and controls.
197 ± 76 68 ± 14 3.0 ± 1.0
Evoked responses Potentiated single twitch (n = 14) 60 ± 24 Twp (Nm) Twp/qCSA (Nm/cm2) 0.89 ± 0.36 Twp maximal rate of force 663 ± 285 development (Nm s−1) Twp maximal rate of force − 243 ± 124 relaxation (Nm s−1) M-wave amplitude (mV) 11 ± 5 M-wave area (mV ms) 0.13 ± 0.06 Potentiated doublets (n = 12) Db100 (Nm) 74 ± 30 1.2 ± 0.5 Db100/qCSA (Nm/cm2) Db10 (Nm) 69 ± 29 Db10/qCSA (Nm/cm2) 1.1 ± 0.5 Db10:100 0.92 ± 0.11 Central parameters VADb (%) (n = 12) 88 ± 8 VATwp (%) (n = 14) 88 ± 8
245 ± 101 78 ± 18 3.2 ± 1.0
69 ± 19 0.88 ± 0.23 712 ± 220 − 232 ± 74 11 ± 4 0.13 ± 0.06
120
P values
110
0.15 0.13 0.57
100
0.28 0.91 0.62
MVC (% Pre values)
MVC (Nm) (n = 15) qCSA (cm2) (n = 14) MVC/qCSA (Nm/cm2) (n = 14)
Controls
* #
90 80 70 60 50
0.78
40
0.99 0.82
30
CF Controls
Pre
10
20
30
40
Exh
P10
Set (% MVC) 97 1.3 90 1.2 0.91
± ± ± ± ±
28 0.5 31 0.4 0.12
93 ± 5 93 ± 5
0.06 0.54 0.11 0.66 0.89 0.11 0.07
Data are given as mean ± SD. Db10 = doublets at 10 Hz; Db100 = doublets at 100 Hz; Db10:100 = ratio between doublets at 10 Hz and 100 Hz; MVC = maximal voluntary contraction; Mmax = maximal M-wave; qCSA = quadriceps cross-sectional area; Twp = potentiated twitch amplitude; VADb = maximal voluntary activation determined from doublets at 100 Hz; VATwp = maximal voluntary activation determined from single twitches.
effect, all P N 0.05). No significant changes over time were observed for Mmax amplitude and area in both groups (time effect, both P N 0.05). VATwp decreased similarly in both groups (time effect, P b 0.05, time × group effect, P = 0.97) while VADb was unchanged (time effect, P = 0.19). Except Db10:100 (time effect, P = 0.41), all contractile parameters showed significant recovery from exhaustion to post 10 (time effect, all P b 0.05) but were still significantly less than Pre (time effect, all P b 0.05, Figs. 2 and 3), without difference between groups (time × group effect, all P N 0.05). VO2peak correlated with MVC (CF, r = 0.66; controls, r = 0.66, both P b 0.05) and total force-time product (CF, r = 0.55; controls, r = 0.64, both P b 0.05) (see Supplementary material). 4. Discussion We found that, as compared with healthy controls, stable CF patients with mild to moderate lung disease have (1) only minor alterations in resting muscle contractility which do not persist when muscle force is expressed relative to qCSA; (2) similar muscle fatigability and underlying mechanisms (i.e., alterations in excitation–contraction coupling). These results do not support our initial hypothesis of an intrinsic CF-related skeletal muscle dysfunction. Some studies investigated muscle strength in both adults and children with CF. The quadriceps muscle was the most studied, probably because of its important functional role. Some studies reported substantial decrease in quadriceps MVC [6, 7] whereas
B
120
*
110
Twp (% Pre values)
CF
A
5
100
#
90 80 70 60 50
CF
40
Controls
30 Pre
10
20
30
40
Exh
P10
Set (% MVC) Fig. 2. Changes in maximum voluntary contraction (MVC, panel A) and potentiated twitch amplitude (Twp, panel B) evoked by femoral nerve magnetic stimulation in the relaxed muscle at baseline (Pre), during the fatiguing task after each set, immediately after exhaustion (Exh) and after 10 min of recovery (P10), in cystic fibrosis (CF) patients (MVC, n = 15; Twp, n = 13) and controls (MVC, n = 15; Twp, n = 13). * Time effect, significantly different from Pre (P b 0.05); # Time effect, significant difference between Exh and P10 (P b 0.05).
other did not [17]. By comparing CF patients with controls matched for PA levels and using both volitional and nonvolitional neuromuscular assessments, our results may explain some of the discrepancies observed in the literature and can provide important insights regarding the mechanisms underlying muscle weakness in CF. We found a non-significant reduction of 24% in quadriceps strength of CF patients. This tendency can be related to reductions in both muscle voluntary activation and contractile function as peripheral (i.e., Db100, P = 0.06) and central parameters (VATwp; P = 0.07) also tended to be reduced in CF. However, these slight non-significant differences all disappeared when expressed relative to qCSA suggesting that reduction in quadriceps strength observed in previous studies can be related to reduction in muscle mass rather than alterations in excitation–contraction coupling. Many factors may potentially contribute to reduced muscle CSA in CF, such as inflammation [18], medication [19], repeated
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
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M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
Fig. 3. Changes in doublets at 100 Hz (DB100, panel A), 10 Hz (Db10, panel B), ratio between doublets at 10 Hz and 100 Hz (Db10:100, panel C) and maximal M-wave amplitude (Mmax, panel D) evoked by femoral nerve magnetic stimulation at baseline (Pre), during the fatiguing task after each set, immediately after exhaustion (Exh) and after 10 min of recovery (P10), in cystic fibrosis (CF) patients (all n = 12, except Mmax, n = 13) and controls (all n = 12, except Mmax, n = 13). * Time effect, significantly different from Pre (P b 0.05); # time effect, significant difference between Exh and P10 (P b 0.05).
exacerbations [20], altered nutritional status [7] or physical inactivity [6]. In our study, we only found a slight tendency for reduced qCSA in CF (14%), which is consistent with previous findings in more severe patients (14%, P = 0.05) [18]. Our patients were clinically stable, did not take oral corticosteroids and had good nutritional status. Moreover, as the degree of systemic inflammation is related to the degree of airway obstruction [21], its role was probably limited in our patients with mild to moderate lung disease, further explaining the absence of substantial reduction in qCSA in our CF population. It has been shown that CF adults are less involved in moderate to vigorous activities despite similar engagement in mild intensities activities [6]. Thus, despite similar global level of PA, we can suppose that the potential slight reductions in qCSA and contractile parameters are in part due to less engagement of our patients in high-intensities or strength activities than controls. Assessment of muscle endurance and fatigability has been very limited in CF. Two studies evaluated quadriceps endurance in CF adults [5, 22]. One reported reduced endurance time in CF during isometric contraction at 50% MVC sustained until
exhaustion [22], whereas another reported smaller number of knee flexions in women but not in men, comparatively to age-matched healthy controls [5]. Both studies have several limitations. First, subjects were not matched for PA level and thus it cannot be excluded that lower levels of habitual PA have contributed to reduced muscle endurance in CF. Second, these measures of endurance were entirely effort-dependent and thus largely influenced by subject's cooperation and motivation. This can explain why CF patients exhibit higher test–retest variability in endurance time than healthy subjects [22]. Finally, these tasks do not permit to distinguish the origin of the mechanisms contributing to increased muscle fatigability. We found similar reductions in MVC throughout the fatiguing task in CF and controls, suggesting similar degree of muscle fatigability in both groups. This can be explained, first, by similar development of peripheral muscle fatigue. M-wave characteristics did not change during the test, indicating that an alteration in neuromuscular propagation of action potentials along the sarcolemma was not involved in muscle fatigability in either CF or controls. Instead, reductions in twitch and doublets indicated contractile fatigue.
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
More specifically, the reduction in Db10:100 indicates low frequency fatigue which is usually associated with a failure in the excitation–contraction coupling since intracellular measurements revealed that low frequency fatigue was due to a reduction in Ca2+ released by the sarcoplasmic reticulum [23]. Moreover, decreased (i) Ca2 + release and/or (ii) sensitivity of the myofilaments to Ca2 + and/or (iii) force produced by each active cross bridge have been constantly associated with reduced muscle force during prolonged isometric exercise [24]. Thus, we suggest that impairment of excitation–contraction coupling, most likely located within the myofibrils, was probably the main factor involved in peripheral fatigue in both CF and controls. As previously reported in healthy subjects [11], our fatiguing exercise induced only small central fatigue (i.e., reduction of voluntary activation of about 5%). Cerebral alterations have been recently reported in COPD and linked to factors such as inflammation, hypoxemia or oxidative stress [25, 26]. However, these factors were unlikely to play a significant role in our CF population, which probably explain the similar kinetics of VATwp and VADb found in both groups, suggesting the absence of specific central alterations in CF patients with mild to moderate lung disease. These similar kinetics and amount of peripheral and central fatigue in both groups are consistent with the similar quadriceps endurance as indicated by the equivalent number of submaximal contractions performed in both groups. Taken together and considering the similar recovery of neuromuscular fatigue in CF and controls, our findings indicate the absence of intrinsic alterations of CF quadriceps muscle. Thus, CF skeletal muscle should demonstrate adequate trainability in response to appropriate stimulus, as we recently demonstrated [27]. Since muscle mass is related to mortality in CF [28], our results should encourage the systematic incorporation of appropriate strength rehabilitation strategies aiming to increase muscle mass, which may in turn have positive effect on functional capacities, quality of life and survival. Wells et al. [9] recently found decreased ATP concentrations and reduced end-exercise intramuscular acidosis in the thigh muscles of CF children as compared to both healthy controls and patients with primary ciliary dyskinesia matched for age and PA levels. However, CF patients achieved the same work rates during a 30-s, 90-s and 5-min exercise test compared to healthy and primary ciliary dyskinesia patients. It is thus possible that the potential intrinsic alterations in the CF muscle, if they exist, do not have functional consequences (i.e., decreased strength and increased fatigability). Alternatively, it is also possible that the class of CFTR mutation may impact the muscle function. For example, Selvadurai et al. [29] demonstrated a relationship between genotype and aerobic capacity, independent of lung function. These issues would require further investigations combining assessments at the cellular levels with measures of muscle fatigability to determine, for instance, whether a given mutation or specific alteration (e.g., lack of CFTR expression in the myocytes [30]) could contribute to increased muscle fatigability. One limitation of the present study was the use of questionnaire to control habitual PA. It has been recently shown that PA levels in CF are better evaluated by accelerometry [31]. However, the
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Baecke questionnaire is one of the most valid questionnaire to evaluate PA [32] and is sensitive to between-group differences [33]. Thus, even if the exact amount of PA may have been slightly misjudged in both groups, we are confident that CF patients were well matched to controls in terms of PA levels. Another limitation is that isometric fatiguing tests do not necessarily reflect daily activities of patients. However, we found that VO2peak determined during CPET was significantly associated to quadriceps force and endurance. Thus, peripheral muscle function may explain in part the reduced aerobic capacity in CF. However, even though the between-group difference was smaller, VO2peak was still reduced when normalized to qCSA in CF patients. The lower breathing reserve at maximum exercise in CF patients indicates that, in addition to muscle strength, respiratory factors have a critical role regarding whole-body exercise limitation in patients with mild to moderate lung disease. 5. Conclusion We demonstrated that CF patients with mild to moderate lung disease have similar muscle endurance and fatigability as compared to healthy subjects. These findings, together with trends for reduced muscle contractility which does not persist when normalized to muscle cross-sectional area, suggest small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) deficit in CF adults. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgments This study was supported by the French Cystic Fibrosis Association (Vaincre La Mucoviscidose) RC20120600744 and partly funded by the French program “Investissement d'Avenir” run by the “Agence Nationale pour la Recherche” grant “Infrastructure d'avenir en Biologie Santé” ANR-11-INBS-0006. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2015.05.004. References [1] Hebestreit H, Schmid K, Kieser S, Junge S, Ballmann M, Roth K, et al. Quality of life is associated with physical activity and fitness in cystic fibrosis. BMC Pulm Med; in press. doi: 10.1186/1471-2466-14-26:14–26. [2] Pianosi P, Leblanc J, Almudevar A. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax 2005;60:50–4. [3] Hulzebos EH, Bomhof-Roordink H, van de Weert-van Leeuwen PB, Twisk JW, Arets HG, van der Ent CK, et al. Prediction of mortality in adolescents with cystic fibrosis. Med Sci Sports Exerc 2014;46:2047–52. [4] Dodd JD, Barry SC, Daly LE, Gallagher CG. Inhaled beta-agonists improve lung function but not maximal exercise capacity in cystic fibrosis. J Cyst Fibros 2005;4:101–5. [5] Sahlberg ME, Svantesson U, Thomas EM, Strandvik B. Muscular strength and function in patients with cystic fibrosis. Chest 2005;127:1587–92.
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[6] Troosters T, Langer D, Vrijsen B, Segers J, Wouters K, Janssens W, et al. Skeletal muscle weakness, exercise tolerance and physical activity in adults with cystic fibrosis. Eur Respir J 2009;33:99–106. [7] de Meer K, Gulmans VA, van Der Laag J. Peripheral muscle weakness and exercise capacity in children with cystic fibrosis. Am J Respir Crit Care Med 1999;159:748–54. [8] Sahlberg M, Svantesson U, Magnusson Thomas E, Andersson BA, Saltin B, Strandvik B. Muscular strength after different types of training in physically active patients with cystic fibrosis. Scand J Med Sci Sports 2008;18:756–64. [9] Wells GD, Wilkes DL, Schneiderman JE, Rayner T, Elmi M, Selvadurai H, et al. Skeletal muscle metabolism in cystic fibrosis and primary ciliary dyskinesia. Pediatr Res 2011;69:40–5. [10] Lamhonwah AM, Bear CE, Huan LJ, Kim Chiaw P, Ackerley CA, Tein I. Cystic fibrosis transmembrane conductance regulator in human muscle: dysfunction causes abnormal metabolic recovery in exercise. Ann Neurol 2010;67:802–8. [11] Bachasson D, Millet GY, Decorte N, Wuyam B, Levy P, Verges S. Quadriceps function assessment using an incremental test and magnetic neurostimulation: a reliability study. J Electromyogr Kinesiol 2013;23: 649–58. [12] Bachasson D, Guinot M, Wuyam B, Favre-Juvin A, Millet GY, Levy P, et al. Neuromuscular fatigue and exercise capacity in fibromyalgia syndrome. Arthritis Care Res 2013;65:432–40. [13] Baecke JA, Burema J, Frijters JE. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr 1982;36:936–42. [14] Henry B, Aussage P, Grosskopf C, Goehrs JM. Development of the Cystic Fibrosis Questionnaire (CFQ) for assessing quality of life in pediatric and adult patients. Qual Life Res 2003;12:63–76. [15] Verges S, Maffiuletti NA, Kerherve H, Decorte N, Wuyam B, Millet GY. Comparison of electrical and magnetic stimulations to assess quadriceps muscle function. J Appl Physiol 2009;106:701–10. [17] Hussey J, Gormley J, Leen G, Greally P. Peripheral muscle strength in young males with cystic fibrosis. J Cyst Fibros 2002;1:116–21. [18] Dufresne V, Knoop C, Van Muylem A, Malfroot A, Lamotte M, Opdekamp C, et al. Effect of systemic inflammation on inspiratory and limb muscle strength and bulk in cystic fibrosis. Am J Respir Crit Care Med 2009;180:153–8. [19] Barry SC, Gallagher CG. Corticosteroids and skeletal muscle function in cystic fibrosis. J Appl Physiol 2003;95:1379–84. [20] Burtin C, Van Remoortel H, Vrijsen B, Langer D, Colpaert K, Gosselink R, et al. Impact of exacerbations of cystic fibrosis on muscle strength. Respir Res 2013;14:46.
[21] Augarten A, Paret G, Avneri I, Akons H, Aviram M, Bentur L, et al. Systemic inflammatory mediators and cystic fibrosis genotype. Clin Exp Med 2004;4:99–102. [22] Gruet M, Vallier JM, Mely L, Brisswalter J. Long term reliability of EMG measurements in adults with cystic fibrosis. J Electromyogr Kinesiol 2010;20:305–12. [23] Hill CA, Thompson MW, Ruell PA, Thom JM, White MJ. Sarcoplasmic reticulum function and muscle contractile character following fatiguing exercise in humans. J Physiol 2001;531:871–8. [24] Place N, Bruton JD, Westerblad H. Mechanisms of fatigue induced by isometric contractions in exercising humans and in mouse isolated single muscle fibres. Clin Exp Pharmacol Physiol 2009;36:334–9. [25] Dodd JW, Chung AW, van den Broek MD, Barrick TR, Charlton RA, Jones PW. Brain structure and function in chronic obstructive pulmonary disease: a multimodal cranial magnetic resonance imaging study. Am J Respir Crit Care Med 2012;186:240–5. [26] Alexandre F, Heraud N, Oliver N, Varray A. Cortical implication in lower voluntary muscle force production in non-hypoxemic COPD patients. PLoS ONE; in press. doi: 10.1371/journal.pone.0100961. eCollection 2014. [27] Vivodtzev I, Decorte N, Wuyam B, Gonnet N, Durieu I, Levy P, et al. Benefits of neuromuscular electrical stimulation prior to endurance training in patients with cystic fibrosis and severe pulmonary dysfunction. Chest 2013;143:485–93. [28] Fogarty AW, Britton J, Clayton A, Smyth AR. Are measures of body habitus associated with mortality in cystic fibrosis? Chest 2012;142: 712–7. [29] Selvadurai HC, McKay KO, Blimkie CJ, Cooper PJ, Mellis CM, Van Asperen PP. The relationship between genotype and exercise tolerance in children with cystic fibrosis. Am J Respir Crit Care Med 2002;165:762–5. [30] Divangahi M, Balghi H, Danialou G, Comtois AS, Demoule A, Ernest S, et al. Lack of CFTR in skeletal muscle predisposes to muscle wasting and diaphragm muscle pump failure in cystic fibrosis mice. PLoS Genet 2009; 5:e1000586. [31] Savi D, Quattrucci S, Internullo M, De Biase RV, Calverley PM, Palange P. Measuring habitual physical activity in adults with cystic fibrosis. Respir Med 2013;107:1888–94. [32] Philippaerts RM, Westerterp KR, Lefevre J. Doubly labelled water validation of three physical activity questionnaires. Int J Sports Med 1999; 20:284–9. [33] Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R. Quantifying physical activity in daily life with questionnaires and motion sensors in COPD. Eur Respir J 2006;27:1040–55.
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
Journal of Cystic Fibrosis xx (2015) xxx – xxx www.elsevier.com/locate/jcf
Original Article
Skeletal muscle contractility and fatigability in adults with cystic fibrosis Mathieu Gruet a,b,c,⁎,1 , Nicolas Decorte a,b,1 , Laurent Mely c,d , Jean-Marc Vallier c , Boubou Camara e , Sébastien Quetant e , Bernard Wuyam a,b,2 , Samuel Verges a,b,2 a
e
Grenoble-Alpes University, HP2 Laboratory, 38000 Grenoble, France b INSERM, U1042, 38000 Grenoble, France c LAMHESS EA 6312, Universities of Toulon and Nice Sophia-Antipolis, France d Regional Cystic Fibrosis Unit (CRCM), Renée Sabran Hospital, Giens, France Regional Cystic Fibrosis Unit (CRCM), Thoracic and Vascular Department, Grenoble University Hospital, France Received 19 February 2015; revised 12 May 2015; accepted 13 May 2015
Abstract Background: Recent discovery of cystic fibrosis transmembrane conductance regulator expression in human skeletal muscle suggests that CF patients may have intrinsic skeletal muscle abnormalities potentially leading to functional impairments. The aim of the present study was to determine whether CF patients with mild to moderate lung disease have altered skeletal muscle contractility and greater muscle fatigability compared to healthy controls. Methods: Thirty adults (15 CF and 15 controls) performed a quadriceps neuromuscular evaluation using single and paired femoral nerve magnetic stimulations. Electromyographic and mechanical parameters during voluntary and magnetically-evoked contractions were recorded at rest, during and after a fatiguing isometric task. Quadriceps cross-sectional area was determined by magnetic resonance imaging. Results: Some indexes of muscle contractility tended to be reduced at rest in CF compared to controls (e.g., mechanical response to doublets stimulation at 100 Hz: 74 ± 30 Nm vs 97 ± 28 Nm, P = 0.06) but all tendencies disappeared when expressed relative to quadriceps cross-sectional area (P N 0.5 for all parameters). CF and controls had similar alterations in muscle contractility with fatigue, similar endurance and post exercise recovery. Conclusions: We found similar skeletal muscle endurance and fatigability in CF adults and controls and only trends for reduced muscle strength in CF which disappeared when normalized to muscle cross-sectional area. These results indicate small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) muscle alterations in CF with mild to moderate lung disease. © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Cystic fibrosis; Skeletal muscle function; Exercise tolerance; Neuromuscular fatigue
1. Background Exercise has many positive effects on various health outcomes in cystic fibrosis (CF) and higher levels of physical fitness are associated with better quality of life [1] and better survival in this
population [2, 3]. Although exercise intolerance is a hallmark of CF disease, the exact underlying mechanisms remain to be elucidated, in particular to optimize exercise rehabilitation programs. It is acknowledged that pulmonary factors alone are insufficient to explain exercise intolerance in CF, especially in
Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CPET, cardiopulmonary exercise test; Db10, potentiated doublets at 10 Hz; Db100, potentiated doublets at 100 Hz; Db10:100, ratio between potentiated doublets at 10 Hz and 100 Hz; FEV1, forced expiratory volume in one second; FMNS, femoral magnetic nerve stimulation; Mmax, maximal M-wave; MVC, maximal voluntary contraction; PA, physical activity; qCSA, quadriceps cross-sectional area; Twp, potentiated twitch amplitude; VA, maximal voluntary activation; VADb, maximal voluntary activation from doublets at 100 Hz; VATwp, maximal voluntary activation from potentiated twitch. ⁎ Corresponding author at: LAMHESS EA 6312, Université de Toulon, BP 20132, 83957 La Garde, France. Tel.: + 33 494142661; fax: +33 494142278. E-mail address: [email protected] (M. Gruet). 1 The first two authors contributed equally to this study. 2 The last two authors shared the senior authorship. http://dx.doi.org/10.1016/j.jcf.2015.05.004 1569-1993© 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
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patients with mild to moderate lung disease. For example, inhaled bronchodilators improve lung function but not maximal exercise capacity in CF [4]. Recent evidence suggests that skeletal muscle dysfunction may play an important role regarding exercise intolerance in CF. Some studies demonstrated a reduction in maximal muscle strength which was related with exercise intolerance in both children and adults with CF [5–7]. This muscle weakness has been traditionally explained by physical inactivity and altered nutritional status. However, muscle weakness observed in a large sample of CF has been found to be in excess to that expected from physical inactivity alone [6]. Moreover, 6 months of endurance and/or resistance training failed to improve muscle strength despite normal nutritional status [8], questioning CF skeletal muscle trainability. Thus, the hypothesis of specific physiological impairments in the CF skeletal muscles can be raised. Wells et al. [9] found abnormalities in muscle metabolism in CF children as compared with age, sex and habitual physical activity (PA)-matched healthy controls, suggesting intrinsic dysfunction of skeletal muscle function. Lamhonwah et al. [10] recently demonstrated that CF transmembrane conductance regulator (CFTR) is expressed at the sarcoplasmic reticulum of human skeletal muscle. It has been proposed that sarcoplasmic reticulum CFTR Cl− channels deficiency could perturb electrochemical gradient, leading to Ca2 + homeostasis dysregulation which could alter excitation– contraction coupling. These data suggest intrinsic CF-related skeletal muscle abnormalities, which may contribute to contractile impairments, increased muscle fatigability and reduced functional capacities in adults with CF. Neuromuscular function can be assessed with artificial muscle stimulation, which allows differentiation between peripheral (i.e., sarcolemmal action potentials propagation, excitation– contraction coupling, contractility) and central (i.e., spinal and/or supraspinal activation of the skeletal muscles) factors accountable for reduced strength and increased fatigability. We recently developed an isolated muscle exercise test which combines voluntary and magnetically-evoked contractions [11]. This test permits to evaluate kinetics of changes in peripheral and central mechanisms of fatigue in a large muscle group (i.e., quadriceps) and limits the influence of motivational factors using progressive loading, non-volitional contractions and multiple assessments. This test is reliable [11] and sensitive to small differences in muscle contractility and fatigability [11, 12]. We hypothesized that CF adults would have altered resting muscle contractility, even when normalized to muscle crosssectional area, and increased muscle fatigability due to exaggerated alterations in excitation–contraction coupling, as compared to age, sex and habitual PA-matched healthy controls. We also hypothesized that these neuromuscular impairments would be associated with reduced exercise tolerance. 2. Methods 2.1. Study population Fifteen adults with CF were recruited from two regional cystic fibrosis units (CRCM Grenoble and CRCM Giens). Main
subjects' characteristics are presented in Table 1. Patients were not included if they were clinically unstable; had contraindications for maximal exercise testing or severe knee condition; had severe pulmonary disease (i.e., forced expiratory volume in one second (FEV1) b 50% of predicted values); were receiving long-term oxygen therapy or corticotherapy or were physically inactive (i.e., less than 60 min of PA per week). Fifteen healthy subjects matched for age, sex and levels of PA were recruited from the hospital staff and visitors to constitute a control group. Written informed consent was obtained and the study was conducted according to the declaration of Helsinki and approved by the local Committee on Human Research (CPP Sud-Est V, Institutional Review Board number n° 1095538) (see Supplementary material for details). 2.2. Experimental design All subjects answered questionnaires, performed a cardiopulmonary exercise test (CPET) and a quadriceps evaluation (e.g., neuromuscular fatigue test and determination of quadriceps cross-sectional area, qCSA) in random order within two days. Habitual PA was measured using the Baecke questionnaire [13]. Health related quality of life was assessed by the French version of the CF questionnaire for adults (CFQ14 +) [14]. CPET was performed using an electronically braked cycle ergometer with breath by breath gas exchanges measurement (see Supplementary material). 2.3. Quadriceps cross-sectional area Subjects underwent magnetic resonance imaging assessment with a 3.0 T whole-body system (Achieva TX, Philips, Amsterdam, Netherlands) to determine qCSA (see Supplementary material). 2.4. Quadriceps neuromuscular evaluation 2.4.1. Experimental set-up All measurements were performed on the right leg under isometric conditions, as previously described [11]. Briefly, subjects laid supine in a custom-built chair with knees at 90° of flexion and the hip angle at 130°. Knee extensor force was measured during voluntary and evoked contractions by calibrated force transducer. Surface EMG signals were recorded from the right vastus lateralis (as a surrogate for the whole quadriceps) according to SENIAM recommendations. Two magnetic stimulators (Magstim 200, The Magstim Company Ltd, Whitland, UK) linked by Bistim Module (Magstim) were used to stimulate the femoral nerve, as previously described [15]. Single (1 Hz, twitch) and paired (10 Hz and 100 Hz doublets) femoral magnetic nerve stimulations (FMNS) of 1-ms duration were delivered via a figure-eight of coil at the maximum stimulator output. The coil was positioned high in the femoral triangle in regard to the femoral nerve and manually controlled by an experienced investigator throughout the protocol (see Supplementary material).
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
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Table 1 Baseline characteristics and questionnaires in CF and controls. CF (n = 15)
Controls (n = 15) 12/3 27 ± 5 22 ± 3
Pancreatic insufficiency, number (%) CF related diabetes, number (%) Glucose intolerance, number (%) Antibiotics therapy, number per year*
12/3 28 ± 6 21 ± 3 9 × ΔF508del hom, 4 × ΔF508del het, 1 × W1089x, 1 × G628R [G → A] 15 (100) 3 (20) 6 (40) 0.6 ± 1.1
Pulmonary function FEV1,L [% pred] FVC, L [% pred] FEV1/FVC,% SVC, L [% pred] TGV, L [% pred] RV, L [% pred] TLC, L [% pred]
2.8 ± 0.9 [72.0] 4.1 ± 0.9 [89.1] 68 ± 11 4.2 ± 1.0 [83.7] 4.1 ± 0.8 [134.2] 2.8 ± 0.7 [180.3] 7.0 ± 1.1 [113.2]
4.3 ± 1.4 [101.6] 5.1 ± 1.1 [102.9] 81 ± 4
2.6 ± 0.5 2.3 ± 0.4 3.2 ± 0.6
2.8 ± 0.2 2.2 ± 0.4 3.6 ± 0.8
Sex, ratio M/F Age, yr BMI, kg/m2 Genotype
Physical activity levels and HRQoL Baecke questionnaire Work index Sport index Leisure-time index CFQ questionnaire Global score (%)
P values 0.43 0.45
b 0.01 b 0.01 b 0.01
0.21 0.43 0.19
79 ± 39
Data are given as mean ± SD. BMI = body mass index; CF = cystic fibrosis; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; HRQoL = health-related quality of life; RV = residual volume; SVC = slow vital capacity; TGV = thoracic gas volume; TLC = total lung capacity; * the year preceding enrollment in the study.
2.4.2. Quadriceps fatigue protocol After quadriceps warm-up (see Supplementary material), subjects performed three maximal voluntary contractions (MVCs) 30 s apart. The initial (Pre-exercise) neuromuscular evaluation was then performed (Fig. 1). It consisted of a 5-s MVC superimposed with 100 Hz doublet and followed after 2 s by two potentiated doublets performed in the relaxed muscle at 100 Hz (Db100) and 10 Hz (Db10) delivered 4 s apart. After 15 s of rest, the subject performed a second MVC with a superimposed twitch followed after 2 s by one potentiated twitch (Twp) in the relaxed muscle. After this Pre-exercise evaluation, subjects performed the fatiguing task which consisted in sets of 10 intermittent (5-s on/ 5-s off) isometric contractions at submaximal target force levels, starting at 10% MVC for the first set and increasing by 10% MVC each set until task failure. The fatiguing task ended when the subject was unable to maintain the target force for more than 2.5 s. Five seconds after the end of each set of 10 contractions, at exhaustion and after 10 min of recovery (Post 10), neuromuscular evaluations similar to the Pre-exercise neuromuscular evaluation were performed. Real-time visual feedback of target force levels and soundtrack indicating the contraction–relaxation rhythm were provided to subjects throughout the experiment (see Supplementary material). 2.5. Data analysis The following peripheral responses to single FMNS were calculated: Twp amplitude, maximal rate of force development
and relaxation and Mmax amplitude and area. The following peripheral responses to paired FMNS were calculated: Db100, Db10 and the ratio Db10:100. All mechanical parameters were also normalized to the qCSA determined by magnetic resonance imaging. Maximal voluntary activation (VA) was calculated by twitch interpolation, from single (VATwp) and paired (VADb) FMNS (see Supplementary material for details). The following parameters were calculated from submaximal contractions: total number of contractions (i.e., the relative endurance index), mean strength and the total force-time product (i.e., the absolute endurance index) calculated over each submaximal contraction. We analyzed data from the 10-contraction sets at 10–40% MVC (i.e., set 10%, 20%, 30% and 40%) as they were completed by all subjects. Changes in voluntary and evoked quadriceps responses from the Pre-exercise neuromuscular evaluation to set 40% and to exhaustion were used as indexes of fatigability. Changes in voluntary and evoked quadriceps responses from exhaustion to post 10 were used as indexes of recovery (see Supplementary material for details). 2.6. Statistics Statistical analyses were conducted with Statistica (version 8, Tulsa, USA). Normality of distribution and homogeneity of variances of main variables were verified using Kolmogorov– Smirnov and Levene tests, respectively. Unpaired t-tests were performed to compare CF and controls for subjects' characteristics, questionnaires scores, CPET and Pre-exercise neuromuscular
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
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M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx 100 Hz 10 Hz 1 Hz Neuromuscular evaluation Task failure
100
MVC (% Pre)
(5-s ON / 5-s OFF) x 10 20 10 0 150 s Pre exercise
Fatiguing exercise Set 10%
Set 20%
Exh
Post 10
Fig. 1. Schematic illustration of the neuromuscular protocol. Pre exercise neuromuscular evaluation consisted of two maximal voluntary contractions (MVC) with femoral nerve magnetic stimulations delivered at different frequencies in both contracted and relaxed muscle. See the text for the exact timing. This neuromuscular evaluation was repeated after each fatiguing set, at exhaustion (Exh) and after 10 min of recovery (Post 10). The fatiguing task consisted of sets of 10 intermittent (5-s on/5-s off) isometric contractions at submaximal target force levels, starting at 10% MVC with increment of 10% MVC each set until exhaustion.
parameters. Changes in mechanical and EMG parameters were analyzed during fatiguing task and recovery by two-way repeated measures ANOVAs (time × group) and Tukey's post-hoc tests. Linear regressions were calculated to investigate whether any relationship existed between neuromuscular and CPET parameters. Statistical significance was set at P b 0.05. Results are given as mean ± standard deviation. 3. Results 3.1. Baseline characteristics and maximal cycling test CF patients were well matched with controls in terms of age and sex and had similar PA levels, as demonstrated by similar scores in the three scales of habitual PA (Table 1). They had similar nutritional status, as suggested by similar body mass index values (Table 1). According to the usual criteria (see Supplementary material), all controls and CF patients performed CPET to a maximal level. CF patients had reduced peak power output, peak oxygen uptake (VO2peak) and higher ventilatory limitation as suggested by higher breathing reserve index at maximum exercise (all P b 0.05; Table 2). CF patients exhibited higher levels of oxygen desaturation than controls (P = 0.01; Table 2). 3.2. Neuromuscular function Despite some slightly reduced values, CF patients had similar qCSA, MVC and peripheral responses to both single and paired FNMS than controls at baseline (Table 3). The small nonsignificant differences disappeared when expressed relative to qCSA. VATwp and VADb did not differ at baseline between the two groups (Table 3).
Total number of submaximal contractions was not different between CF and controls (52 ± 6 vs 55 ± 8, respectively, P = 0.26). However, total force-time product was significantly smaller in CF as compared to controls (15,370 ± 5925 Nm s−1 vs 21,627 ± 9089 Nm s−1, respectively, P = 0.03). This difference disappeared when expressed relative to qCSA (P = 0.18). MVC and Twp kinetics in both groups are shown in Fig. 2. Db100, Db10, Db10:100 and Mmax amplitude kinetics in both groups are shown in Fig. 3. All peripheral mechanical parameters decreased over time in both groups (time effect, all P b 0.05), without difference between groups (time × group Table 2 Maximal aerobic capacities in CF and controls. CF (n = 15) Peak power output, W VO2peak, L min−1 [% pred] VO2peak, mL min−1 kg−1 VO2peak/qCSA, mL min−1/cm2 VO2VT, L min−1 Maximal minute ventilation, L min−1 BRImax Maximal heart rate, bpm [% pred] Oxygen desaturation (%) Maximal [La−], mmol L−1 Peak rate of perceived exertion Breathlessness Muscle fatigue
186 2.3 37 34 1.6 93
± ± ± ± ± ±
Controls (n = 15)
58 296 0.7 [87.6] 3.2 10 46 9 43 0.5 2.4 21 136
± ± ± ± ± ±
71 1.0 [106] 6 8 0.6 28
P values b 0.01 b 0.01 b 0.01 b 0.01 b 0.01 b 0.01
0.98 ± 0.12 172 ± 9 [90]
0.85 ± 0.13 189 ± 7 [98]
0.01 b 0.01
2.6 ± 2.8 10.5 ± 3.0
0.5 ± 0.8 11.7 ± 2.6
0.01 0.27
88 ± 13 88 ± 15
81 ± 21 87 ± 14
0.36 0.92
Data are given as mean ± SD. BRImax = breathing reserve index at maximum exercise; CF = cystic fibrosis; qCSA = quadriceps cross-sectional area; VO2peak = peak oxygen consumption; VO2VT = oxygen consumption at the first ventilatory threshold; [La−] = blood lactate concentration.
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx Table 3 Baseline neuromuscular function in CF and controls.
197 ± 76 68 ± 14 3.0 ± 1.0
Evoked responses Potentiated single twitch (n = 14) 60 ± 24 Twp (Nm) Twp/qCSA (Nm/cm2) 0.89 ± 0.36 Twp maximal rate of force 663 ± 285 development (Nm s−1) Twp maximal rate of force − 243 ± 124 relaxation (Nm s−1) M-wave amplitude (mV) 11 ± 5 M-wave area (mV ms) 0.13 ± 0.06 Potentiated doublets (n = 12) Db100 (Nm) 74 ± 30 1.2 ± 0.5 Db100/qCSA (Nm/cm2) Db10 (Nm) 69 ± 29 Db10/qCSA (Nm/cm2) 1.1 ± 0.5 Db10:100 0.92 ± 0.11 Central parameters VADb (%) (n = 12) 88 ± 8 VATwp (%) (n = 14) 88 ± 8
245 ± 101 78 ± 18 3.2 ± 1.0
69 ± 19 0.88 ± 0.23 712 ± 220 − 232 ± 74 11 ± 4 0.13 ± 0.06
120
P values
110
0.15 0.13 0.57
100
0.28 0.91 0.62
MVC (% Pre values)
MVC (Nm) (n = 15) qCSA (cm2) (n = 14) MVC/qCSA (Nm/cm2) (n = 14)
Controls
* #
90 80 70 60 50
0.78
40
0.99 0.82
30
CF Controls
Pre
10
20
30
40
Exh
P10
Set (% MVC) 97 1.3 90 1.2 0.91
± ± ± ± ±
28 0.5 31 0.4 0.12
93 ± 5 93 ± 5
0.06 0.54 0.11 0.66 0.89 0.11 0.07
Data are given as mean ± SD. Db10 = doublets at 10 Hz; Db100 = doublets at 100 Hz; Db10:100 = ratio between doublets at 10 Hz and 100 Hz; MVC = maximal voluntary contraction; Mmax = maximal M-wave; qCSA = quadriceps cross-sectional area; Twp = potentiated twitch amplitude; VADb = maximal voluntary activation determined from doublets at 100 Hz; VATwp = maximal voluntary activation determined from single twitches.
effect, all P N 0.05). No significant changes over time were observed for Mmax amplitude and area in both groups (time effect, both P N 0.05). VATwp decreased similarly in both groups (time effect, P b 0.05, time × group effect, P = 0.97) while VADb was unchanged (time effect, P = 0.19). Except Db10:100 (time effect, P = 0.41), all contractile parameters showed significant recovery from exhaustion to post 10 (time effect, all P b 0.05) but were still significantly less than Pre (time effect, all P b 0.05, Figs. 2 and 3), without difference between groups (time × group effect, all P N 0.05). VO2peak correlated with MVC (CF, r = 0.66; controls, r = 0.66, both P b 0.05) and total force-time product (CF, r = 0.55; controls, r = 0.64, both P b 0.05) (see Supplementary material). 4. Discussion We found that, as compared with healthy controls, stable CF patients with mild to moderate lung disease have (1) only minor alterations in resting muscle contractility which do not persist when muscle force is expressed relative to qCSA; (2) similar muscle fatigability and underlying mechanisms (i.e., alterations in excitation–contraction coupling). These results do not support our initial hypothesis of an intrinsic CF-related skeletal muscle dysfunction. Some studies investigated muscle strength in both adults and children with CF. The quadriceps muscle was the most studied, probably because of its important functional role. Some studies reported substantial decrease in quadriceps MVC [6, 7] whereas
B
120
*
110
Twp (% Pre values)
CF
A
5
100
#
90 80 70 60 50
CF
40
Controls
30 Pre
10
20
30
40
Exh
P10
Set (% MVC) Fig. 2. Changes in maximum voluntary contraction (MVC, panel A) and potentiated twitch amplitude (Twp, panel B) evoked by femoral nerve magnetic stimulation in the relaxed muscle at baseline (Pre), during the fatiguing task after each set, immediately after exhaustion (Exh) and after 10 min of recovery (P10), in cystic fibrosis (CF) patients (MVC, n = 15; Twp, n = 13) and controls (MVC, n = 15; Twp, n = 13). * Time effect, significantly different from Pre (P b 0.05); # Time effect, significant difference between Exh and P10 (P b 0.05).
other did not [17]. By comparing CF patients with controls matched for PA levels and using both volitional and nonvolitional neuromuscular assessments, our results may explain some of the discrepancies observed in the literature and can provide important insights regarding the mechanisms underlying muscle weakness in CF. We found a non-significant reduction of 24% in quadriceps strength of CF patients. This tendency can be related to reductions in both muscle voluntary activation and contractile function as peripheral (i.e., Db100, P = 0.06) and central parameters (VATwp; P = 0.07) also tended to be reduced in CF. However, these slight non-significant differences all disappeared when expressed relative to qCSA suggesting that reduction in quadriceps strength observed in previous studies can be related to reduction in muscle mass rather than alterations in excitation–contraction coupling. Many factors may potentially contribute to reduced muscle CSA in CF, such as inflammation [18], medication [19], repeated
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
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Fig. 3. Changes in doublets at 100 Hz (DB100, panel A), 10 Hz (Db10, panel B), ratio between doublets at 10 Hz and 100 Hz (Db10:100, panel C) and maximal M-wave amplitude (Mmax, panel D) evoked by femoral nerve magnetic stimulation at baseline (Pre), during the fatiguing task after each set, immediately after exhaustion (Exh) and after 10 min of recovery (P10), in cystic fibrosis (CF) patients (all n = 12, except Mmax, n = 13) and controls (all n = 12, except Mmax, n = 13). * Time effect, significantly different from Pre (P b 0.05); # time effect, significant difference between Exh and P10 (P b 0.05).
exacerbations [20], altered nutritional status [7] or physical inactivity [6]. In our study, we only found a slight tendency for reduced qCSA in CF (14%), which is consistent with previous findings in more severe patients (14%, P = 0.05) [18]. Our patients were clinically stable, did not take oral corticosteroids and had good nutritional status. Moreover, as the degree of systemic inflammation is related to the degree of airway obstruction [21], its role was probably limited in our patients with mild to moderate lung disease, further explaining the absence of substantial reduction in qCSA in our CF population. It has been shown that CF adults are less involved in moderate to vigorous activities despite similar engagement in mild intensities activities [6]. Thus, despite similar global level of PA, we can suppose that the potential slight reductions in qCSA and contractile parameters are in part due to less engagement of our patients in high-intensities or strength activities than controls. Assessment of muscle endurance and fatigability has been very limited in CF. Two studies evaluated quadriceps endurance in CF adults [5, 22]. One reported reduced endurance time in CF during isometric contraction at 50% MVC sustained until
exhaustion [22], whereas another reported smaller number of knee flexions in women but not in men, comparatively to age-matched healthy controls [5]. Both studies have several limitations. First, subjects were not matched for PA level and thus it cannot be excluded that lower levels of habitual PA have contributed to reduced muscle endurance in CF. Second, these measures of endurance were entirely effort-dependent and thus largely influenced by subject's cooperation and motivation. This can explain why CF patients exhibit higher test–retest variability in endurance time than healthy subjects [22]. Finally, these tasks do not permit to distinguish the origin of the mechanisms contributing to increased muscle fatigability. We found similar reductions in MVC throughout the fatiguing task in CF and controls, suggesting similar degree of muscle fatigability in both groups. This can be explained, first, by similar development of peripheral muscle fatigue. M-wave characteristics did not change during the test, indicating that an alteration in neuromuscular propagation of action potentials along the sarcolemma was not involved in muscle fatigability in either CF or controls. Instead, reductions in twitch and doublets indicated contractile fatigue.
Please cite this article as: Gruet M, et al, Skeletal muscle contractility and fatigability in adults with cystic fibrosis, J Cyst Fibros (2015), http://dx.doi.org/10.1016/ j.jcf.2015.05.004
M. Gruet et al. / Journal of Cystic Fibrosis xx (2015) xxx–xxx
More specifically, the reduction in Db10:100 indicates low frequency fatigue which is usually associated with a failure in the excitation–contraction coupling since intracellular measurements revealed that low frequency fatigue was due to a reduction in Ca2+ released by the sarcoplasmic reticulum [23]. Moreover, decreased (i) Ca2 + release and/or (ii) sensitivity of the myofilaments to Ca2 + and/or (iii) force produced by each active cross bridge have been constantly associated with reduced muscle force during prolonged isometric exercise [24]. Thus, we suggest that impairment of excitation–contraction coupling, most likely located within the myofibrils, was probably the main factor involved in peripheral fatigue in both CF and controls. As previously reported in healthy subjects [11], our fatiguing exercise induced only small central fatigue (i.e., reduction of voluntary activation of about 5%). Cerebral alterations have been recently reported in COPD and linked to factors such as inflammation, hypoxemia or oxidative stress [25, 26]. However, these factors were unlikely to play a significant role in our CF population, which probably explain the similar kinetics of VATwp and VADb found in both groups, suggesting the absence of specific central alterations in CF patients with mild to moderate lung disease. These similar kinetics and amount of peripheral and central fatigue in both groups are consistent with the similar quadriceps endurance as indicated by the equivalent number of submaximal contractions performed in both groups. Taken together and considering the similar recovery of neuromuscular fatigue in CF and controls, our findings indicate the absence of intrinsic alterations of CF quadriceps muscle. Thus, CF skeletal muscle should demonstrate adequate trainability in response to appropriate stimulus, as we recently demonstrated [27]. Since muscle mass is related to mortality in CF [28], our results should encourage the systematic incorporation of appropriate strength rehabilitation strategies aiming to increase muscle mass, which may in turn have positive effect on functional capacities, quality of life and survival. Wells et al. [9] recently found decreased ATP concentrations and reduced end-exercise intramuscular acidosis in the thigh muscles of CF children as compared to both healthy controls and patients with primary ciliary dyskinesia matched for age and PA levels. However, CF patients achieved the same work rates during a 30-s, 90-s and 5-min exercise test compared to healthy and primary ciliary dyskinesia patients. It is thus possible that the potential intrinsic alterations in the CF muscle, if they exist, do not have functional consequences (i.e., decreased strength and increased fatigability). Alternatively, it is also possible that the class of CFTR mutation may impact the muscle function. For example, Selvadurai et al. [29] demonstrated a relationship between genotype and aerobic capacity, independent of lung function. These issues would require further investigations combining assessments at the cellular levels with measures of muscle fatigability to determine, for instance, whether a given mutation or specific alteration (e.g., lack of CFTR expression in the myocytes [30]) could contribute to increased muscle fatigability. One limitation of the present study was the use of questionnaire to control habitual PA. It has been recently shown that PA levels in CF are better evaluated by accelerometry [31]. However, the
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Baecke questionnaire is one of the most valid questionnaire to evaluate PA [32] and is sensitive to between-group differences [33]. Thus, even if the exact amount of PA may have been slightly misjudged in both groups, we are confident that CF patients were well matched to controls in terms of PA levels. Another limitation is that isometric fatiguing tests do not necessarily reflect daily activities of patients. However, we found that VO2peak determined during CPET was significantly associated to quadriceps force and endurance. Thus, peripheral muscle function may explain in part the reduced aerobic capacity in CF. However, even though the between-group difference was smaller, VO2peak was still reduced when normalized to qCSA in CF patients. The lower breathing reserve at maximum exercise in CF patients indicates that, in addition to muscle strength, respiratory factors have a critical role regarding whole-body exercise limitation in patients with mild to moderate lung disease. 5. Conclusion We demonstrated that CF patients with mild to moderate lung disease have similar muscle endurance and fatigability as compared to healthy subjects. These findings, together with trends for reduced muscle contractility which does not persist when normalized to muscle cross-sectional area, suggest small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) deficit in CF adults. Conflict of interest The authors have no conflicts of interest to declare. Acknowledgments This study was supported by the French Cystic Fibrosis Association (Vaincre La Mucoviscidose) RC20120600744 and partly funded by the French program “Investissement d'Avenir” run by the “Agence Nationale pour la Recherche” grant “Infrastructure d'avenir en Biologie Santé” ANR-11-INBS-0006. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.jcf.2015.05.004. References [1] Hebestreit H, Schmid K, Kieser S, Junge S, Ballmann M, Roth K, et al. Quality of life is associated with physical activity and fitness in cystic fibrosis. BMC Pulm Med; in press. doi: 10.1186/1471-2466-14-26:14–26. [2] Pianosi P, Leblanc J, Almudevar A. Peak oxygen uptake and mortality in children with cystic fibrosis. Thorax 2005;60:50–4. [3] Hulzebos EH, Bomhof-Roordink H, van de Weert-van Leeuwen PB, Twisk JW, Arets HG, van der Ent CK, et al. Prediction of mortality in adolescents with cystic fibrosis. Med Sci Sports Exerc 2014;46:2047–52. [4] Dodd JD, Barry SC, Daly LE, Gallagher CG. Inhaled beta-agonists improve lung function but not maximal exercise capacity in cystic fibrosis. J Cyst Fibros 2005;4:101–5. [5] Sahlberg ME, Svantesson U, Thomas EM, Strandvik B. Muscular strength and function in patients with cystic fibrosis. Chest 2005;127:1587–92.
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