JAMDA xxx (2014) 1e5

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Original Study

Motoneuron Loss Is Associated With Sarcopenia Michael Drey MD, MSc a, *, Benjamin Krieger MD a, Cornel C. Sieber MD a, Jürgen M. Bauer MD a, b, Stefan Hettwer PhD c, Thomas Bertsch MD d, the DISARCO Study Groupy a

University of Erlangen-Nuremberg, Institute for Biomedicine of Ageing, Nuremberg, Germany Klinikum Oldenburg, Geriatric Centre Oldenburg, Oldenburg, Germany c Neurotune AG, Schlieren, Switzerland d Klinikum Nuremberg, Institute for Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, Nuremberg, Germany e Hochschule für Technik Rapperswil, Rapperswil, Switzerland b

a b s t r a c t Keywords: Sarcopenia motoneuron MUNIX

Objectives: Sarcopenia, age-related muscle wasting, is associated with increased morbidity and mortality in the affected individuals. The pathogenesis of sarcopenia is not yet fully understood. A multifactorial concept is currently favored. The reduced number of motor units as a potential mechanism of muscle mass loss is explored in the present study. Design: This is a cross-sectional study. Setting: The participants were community-dwelling older adults. Participants: The participants were sarcopenic (75) and nonsarcopenic (74) according to the criteria of the European Working Group on Sarcopenia in Older People aged 65 to 94 years. Measurements: The motor unit number index (MUNIX) of the hypothenar muscle was used to assess the number and size [motor unit size index (MUSIX)] of motor units. Results: The participants with pathologic MUNIX and MUSIX (n ¼ 23) are significantly more frequently sarcopenic (n ¼ 17, P ¼ .029) than nonsarcopenic (n ¼ 6). The participants with pathologic MUNIX and MUSIX (n ¼ 23) had significantly less muscle mass than the nonsarcopenic controls (P < .001). After adjusting for age and sex, only gait speed has shown no difference between the 2 groups. Pearson’s correlation coefficient between MUSIX and the reciprocal value of MUNIX is 0.87 (P < .001). Conclusions: Sarcopenia induced by a small number of motoneurons can be identified by applying the MUNIX method to the hypothenar muscle. An enlargement of motor units because of motoneuron loss seems to preserve physical performance. Ó 2014 - American Medical Directors Association, Inc. All rights reserved.

In aging societies, age-related muscle wasting (sarcopenia) is becoming an increasingly serious medical and economic problem. Sarcopenia is evident in around 20% of over 70-year-olds; this figure rises to 50% in the over-80 age group.1 Those affected exhibit greater morbidity and mortality.2 The pathomechanism that leads to

The “DISARCO” project was carried out within the Eurostars Programme. The German partners were funded by the German Federal Ministry of Education and Research (BMBF). The authors declare no conflicts of interest. * Address correspondence to Michael Drey, MD, MSc, University of ErlangenNuremberg, Institute for Biomedicine of Ageing, Heimerichstrasse 58, 90419 Nuremberg, Germany. E-mail address: [email protected] (M. Drey). y DISARCO Study Group: Pius Dahindenc, Armin Mäder PhD c, Jan Willem Vrijbloed PhD c, Guido Schuster PhD e, Stefan Zollingere, Christoph Beelere, Thomas Unterere

sarcopenia has not yet been identified. The prevailing concept for explaining the development of sarcopenia is multifactorial.3 The loss of motoneurons in the spinal cord in the genesis of sarcopenia is discussed within this concept.4 Downstream muscle fibers degenerate because of the age-related loss of motoneurons. This degeneration of motor units (MUs) ultimately leads to a loss of muscle mass, resulting in sarcopenia. By applying the motor unit number index (MUNIX), the number of motoneurons in sarcopenic patients can be determined from a muscle.5 MUNIX is an electromyographic method for assessing the number and size [motor unit size index (MUSIX)] of MUs using the compound muscle action potential (CMAP) and the surface electromyographic interference pattern (SIP).6 In the present study, the MUNIX technique is used to demonstrate that having a small quantity of motoneurons is accompanied by low muscle mass. In addition, the relevance of this pathomechanism to the clinical picture of sarcopenia will be shown.

1525-8610/$ - see front matter Ó 2014 - American Medical Directors Association, Inc. All rights reserved. http://dx.doi.org/10.1016/j.jamda.2014.02.002

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M. Drey et al. / JAMDA xxx (2014) 1e5

Methods Participants A total of 75 sarcopenic and 75 nonsarcopenic communitydwelling elderly over the age of 65 were to be recruited for the present investigation. In the first phase, participants were recruited following the publication of a newspaper advertisement. Of the 158 respondents, 70 were ineligible (see below for exclusion criteria) or unwilling to participate in the study. Hence, 88 participants (38 sarcopenic and 50 nonsarcopenic) were recruited for the study in the first phase. In the second phase, recruitment was continued by screening patient archives at the affiliated geriatric day clinic from the past 2 years (1090 patients) for eligible participants until the planned number of participants had been reached (37 sarcopenic and 24 nonsarcopenic participants). Finally, a total of 149 individuals (75 sarcopenic and 74 nonsarcopenic) were recruited. Muscle mass was calculated using Janssen’s regression formula by applying bioelectrical impedance analysis.7 To classify sarcopenia, muscle mass was divided by squared body height (kg/m2). Thresholds for muscle mass were 6.42 kg/m2 for women and 8.87 kg/m2 for men.8,9 Handgrip strength was determined by using a hand-held dynamometer (JAMAR, Los Angeles, CA). Thresholds for grip strength were 20 kg for women and 30 kg for men. The cut-off for gait speed (over a 4 m course) was 1 m/s.9 Participants were classified as being sarcopenic by low muscle mass and low grip strength or low gait speed. Severe sarcopenia was identified by low muscle mass, low grip strength, and low gait speed. Presarcopenic participants were classified as those who have only low muscle mass.9 Participants who (1) had intentionally or unintentionally lost more than 5% of their body weight over the last 3 months, (2) had suffered from active cancer in the 5 years prior to the study, (3) had suffered specific muscular disorders or any kind of neuropathy, or (4) were unable to give their consent were excluded from the study. The study was approved by the Medical Ethics Committee of the University Erlangen-Nürnberg. All participants gave their informed consent.

MUNIX is based on a mathematical model, described for the first time by Nandedkar using the CMAP and SIP of the hypothenar muscle.6 MUNIX is a 3-step procedure. First, the CMAP is recorded by supramaximal stimulation of the ulnar nerve. The active electrode is placed over the motor point of the right hypothenar muscle. The reference electrode is placed on the distal phalanx of the little finger; the ground electrode is fixed to the wrist of the hand. Three consecutive supramaximal stimulations are performed to obtain the highest possible CMAP amplitude. The negative phase of the CMAP is used to calculate its amplitude, area, and power. The SIPs are recorded in the second step. Each SIP epoch is 300 ms long. The patient is then instructed to exert and maintain an isometric contraction at varying levels of effort. The progressive series of resistance is repeated to obtain 18 different SIP epochs. The CMAP and SIP are recorded using a bandpass filter setting of 3e3000 Hz. In the final step, the CMAP and SIP signals are imported to the analysis software written by Nandedkar,6 which calculates the area and power of the signals. The “ideal case motor unit count” (ICMUC) is computed using AreaðSIP Þ PowerðCMAP Þ PowerðSIP Þ  AreaðCMAP Þ .

MUSIX ¼

AmplitudeðCMAPÞ MUNIX

MUSIX, measured in microvolts, represents the average amplitude of a single surface-recorded motor unit potential. It should be stressed that MUNIX and MUSIX are indices of the number and size of MUs, and are not absolute values. Prior to the analysis, the operator views the SIP epochs to identify all artifacts, such as highfrequency noise, power line frequency interference, baseline shifts, and tremor. If artifacts are significant, the epoch is rejected from the analysis. If there is no apparent voluntary electromyographic activity, the SIP will have a low but finite area and power value. This results in a very high false ICMUC value. To prevent this, we used the following three criteria to accept an SIP epoch, as proposed by Nandedkar10: (1) SIP area >20 mVms; (2) ICMUC 1. Statistical Analysis PASW 21.0 (IBM-SPSS Inc, Chicago, IL) was used for statistical analysis. The participants’ characteristics were expressed as the mean and standard deviation (Table 1). Multiple linear regression analysis was used to describe group differences between participants with pathologic MUNIX/MUSIX and nonsarcopenic controls in muscle mass, handgrip strength and gait speed, adjusted for age and sex (Tables 2 and 3). The influence of pathologic MUNIX/MUSIX values on the presence of sarcopenia, adjusted for age and sex, was calculated by logistic regression (Table 4). Correlation between MUSIX and the reciprocal value of MUNIX was expressed by Pearson’s correlation coefficient (Figure 1). The level of significance was set at 5%. Results

The MUNIX Technique

ICMUC ¼

The SIP area value of 20 mVms is chosen arbitrarily, based on the observation that very slight activity, produced by a few motor units, has an SIP area of around 20 mVms.10 The assumptions of the model are adequately satisfied for an SIP area of 20 mVms. MUSIX is obtained by dividing the CMAP amplitude by MUNIX:

The relationship between ICMUC

and SIP area (ICMUC ¼ A  ðAreaðSIP ÞÞa ) is modelled by a power function in SPSS 21.0 (IBM-SPSS Inc, Chicago, IL). The values of A and a are derived from a regression analysis fitting the power function. The regression curve characterises the tested muscle. Finally, MUNIX is calculated using: MUNIX ¼ A  ð20mVmsÞa .

The participants’ characteristics are shown in Table 1. Figure 1 shows the relationship between MUNIX and MUSIX in the study participants. Pearson’s correlation coefficient between MUSIX and the reciprocal value of MUNIX is 0.87 (P < .001). The solid line in Figure 1 indicates the reciprocal relationship. The upper left cluster shows 23 participants with pathologic MUNIX (100mV), 17 Table 1 Characteristics of Participants Nonsarcopenic Sarcopenic Participants* Controls ntotal ¼ 74, nfemale ¼ 38

Measurement Mean (SD) Age (years) 76 (5.4) SM (kg) 24 (6.3) SMI (kg/m2) 8.5 (1.5) Grip strength (kg) 31 (12) Gait speed (m/s) 1.1 (0.3) MUNIX 119 (40) MUSIX (mV) 95 (33)

Presarcopenia Sarcopenia Severe ntotal ¼ 20, Sarcopenia ntotal ¼ 22, nfemale ¼ 11 nfemale ¼ 13 ntotal ¼ 32, nfemale ¼ 21 Mean (SD) 75 (5.6) 20 (5.4) 7.0 (1.4) 31 (8.3) 1.3 (0.2) 118 (41) 95 (31)

Mean (SD) 75 (6.1) 19 (5.9) 6.8 (1.3) 26 (7.2) 1.0 (0.2) 117 (36) 97 (27)

Mean (SD) 82 (5.1) 18 (4.8) 6.7 (1.2) 18 (6.0) 0.7 (0.2) 101 (42) 108 (47)

MUNIX, motor unit number index; MUSIX, motor unit size index; SD, standard deviation; SM, skeletal muscle mass; SMI, skeletal muscle index. *One participant could not be classified because of missing grip strength and gait speed.

M. Drey et al. / JAMDA xxx (2014) 1e5 Table 2 Differences Between Participants With Pathologic MUNIX/MUSIX and Nonsarcopenic Controls

Measurement Age (years) MUNIX MUSIX (mV) SM (kg) SMI (kg/m2) Handgrip (kg) Gaitspeed (m/s)

Nonsarcopenic Controls* ntotal ¼ 68, nfemale ¼ 34

Participants With Pathologic MUNIX/MUSIX ntotal ¼ 23, nfemale ¼ 16

Mean (SD) 76 (5.4) 124 (38) 89 (22) 25 (6.4) 8.6 (1.5) 31 (12) 1.0 (0.3)

Mean (SD) 79 (7.5) 61 (11) 159 (40) 18 (5.1) 6.9 (1.3) 24 (10) 0.9 (0.3)

Table 4 Unadjusted and Adjusted Logistic Regression for Sarcopenia as an Outcome Model Variable 1 2

P Value .033 .001, .001y .001, .001y .001, .001y .001, .001y .013, .191y .108, .740y

MUNIX, motor unit number index; MUSIX, motor unit size index; SD, standard deviation; SM, skeletal muscle mass; SMI, skeletal muscle index. *Six nonsarcopenic participants are among the “Participants with pathologic MUNIX/MUSIX.” y Adjusted for age and sex.

3

ny

Regression Odds 95% CI Coefficient Ratio

Pathologic MUNIX/MUSIX 147 1.24 Pathologic MUNIX/MUSIX* 147 1.13

3.44 3.09

P Value

1.27e9.31 .015 1.12e8.48 .029

MUNIX, motor unit number index; MUSIX, motor unit size index. *Adjusted for age and sex. y Two participants did not tolerate MUNIX measurement.

Discussion In the present study, the MUNIX technique was used to identify a subset of sarcopenic participants by a small quantity of motor units in the hypothenar muscle. In participants with a small quantity of motor units, enlargement of the remaining motor units seems to be a mechanism of compensation and could be a starting point for the pharmacologic treatment of sarcopenia. Neurogenic View of Muscle Loss

of whom belong to the sarcopenic group (3 presarcopenia, 3 sarcopenia, 11 severe sarcopenia); 6 participants are nonsarcopenic. The group comparison (c2 test) between “participants with pathologic/ normal MUNIX/MUSIX values” vs “participants with sarcopenia/ nonsarcopenia” reveals significantly (P ¼ .011) more frequent sarcopenic participants with pathologic MUNIX/MUSIX values. Table 2 shows differences between participants with pathologic MUNIX/MUSIX and nonsarcopenic controls in muscle mass, handgrip strength, and gait speed. After adjusting for age and sex, only muscle mass differed significantly between the 2 groups. The nonsarcopenic group consists of 68 rather than 74 participants because 6 nonsarcopenic participants exhibited pathologic MUNIX/MUSIX values. Table 3 shows the differences between sarcopenic participants with pathologic MUNIX/MUSIX and nonsarcopenic controls with regard to muscle mass, handgrip strength, and gait speed. This table differs from Table 2 in that it classifies the 6 nonsarcopenic participants with pathologic MUNIX/MUSIX as nonsarcopenic controls. All values differ significantly between the 2 groups, with the exception of adjusted gait speed. Table 4 shows the results for logistic regression with sarcopenia (presarcopenia, sarcopenia, severe Sarcopenia) as the outcome. The odds ratio for being sarcopenic with pathologic MUNIX and MUSIX values is 3.44 (1.27e9.31) (model one). For the same model, but adjusted for age and sex, the odds ratio is 3.09 (1.12e8.48) (model 2). Two participants could not tolerate MUNIX measurement. The logistic regression was therefore calculated using the measurements from 147 participants only.

The pathogenesis of sarcopenia is not yet fully understood. A musculocentric approach assumes that an earlier loss of muscle fibers is the cause of sarcopenia. If the degeneration of the neuromuscular junction is dominant, this is referred to as a synaptocentric perspective. If the loss of nerve cells is the focus of the development of sarcopenia, there is a neurocentric pathogenesis. It would also be conceivable to combine all 3 factors when considering the genesis of sarcopenia. In the present study, proof of motoneuron loss (neurocentric approach) is primarily seen as the cause of sarcopenia.11 Previous research revealed that the quantity of motor units declines with age,12,13 whereas the remaining motor units increase in size.14,15 However, no connection to sarcopenia was established. The number (MUNIX) and size (MUSIX) of a muscle’s motor units can be determined by applying the MUNIX technique developed by Nandedkar et al.6 This technique was originally devised to evaluate the course of amyotrophic lateral sclerosis (ALS), in which a muscledfrequently the hypothenar muscledtypically serves as an indicator muscle for the systemic loss of motoneurons.16,17 Investigations demonstrated that the MUNIX technique can be applied to the hypothenar muscle of sarcopenic patients.5 It should be stressed that MUNIX and MUSIX are indices of the number and size of MUs and are not absolute values. Nandedkar et al determined cut-off values for MUNIX and MUSIX for the hypothenar muscle in healthy subjects. Consequently,

Table 3 Differences Between Sarcopenic Participants With Pathologic MUNIX/MUSIX and Nonsarcopenic Controls

Measurement Age (years) MUNIX MUSIX (mV) SM (kg) SMI (kg/m2) Handgrip (kg) Gaitspeed (m/s)

Nonsarcopenic Controls ntotal ¼ 74, nfemale ¼ 38

Sarcopenic participants With Pathologic MUNIX/MUSIX ntotal ¼ 17, nfemale ¼ 12

Mean (SD) 76 (5.4) 119 (40) 95 (33) 24 (6.3) 8.5 (1.5) 31 (12) 1.1 (0.3)

Mean (SD) 80 (8.2) 60 (10) 157 (36) 17 (4.7) 6.5 (1.0) 22 (9.2) 0.9 (0.2)

P Value .032

Motoneuron loss is associated with sarcopenia.

Sarcopenia, age-related muscle wasting, is associated with increased morbidity and mortality in the affected individuals. The pathogenesis of sarcopen...
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