5043
J Physiol 594.18 (2016) pp 5043–5044
JOURNAL CLUB
Delineating the effects of aerobic training versus aerobic capacity on satellite cell behaviour in humans Kevin A. Murach Center for Muscle Biology and Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, Lexington, KY 40536, USA
The Journal of Physiology
Email: [email protected]
Since the initial characterization of muscle stem cells (satellite cells) in 1961, significant time and energy has been dedicated to uncovering their function in skeletal muscle. Over 50 years later, researchers are still elucidating the role(s) satellite cells play in exercise adaptation, ageing, health and disease. Satellite cells are indisputably necessary for regeneration (i.e. successful recovery from injury), but their requirement as myonuclear donors during adult skeletal muscle hypertrophy has been challenged using an inducible satellite cell knockout mouse (McCarthy et al. 2011). Depletion of satellite cells prior to endurance training in adult mice does not affect fibre type transitioning or muscle aerobic adaptations, but does affect coordination and running performance by disrupting intrafusal fibre (i.e. muscle spindle) morphology and activity (Jackson et al. 2015). Satellite cells play a homeostatic role by contributing to muscle fibres (Keefe et al. 2015) and regulating fibrosis (Fry et al. 2015) throughout the lifespan in sedentary mice, but do not appear to mediate sarcopenia with ageing (Fry et al. 2015; Keefe et al. 2015). Transgenic mouse models that permit post-developmental manipulation of satellite cells in conjunction with rodent muscle training techniques provide invaluable information on satellite cell biology and behaviour, but the question of translatability to humans is always pertinent. To that point, a multitude of human research indicates that satellite cell activity and density increases profoundly in response to varying environmental stimuli (e.g. exercise), strongly signifying an active role in the muscle adaptive process. Most recently, how satellite cells interact with secreted factors as well as their influence on muscle fibre type-specific adaptations
to exercise (e.g. slow versus fast twitch) has emerged as an area of inquiry in humans. In a recent issue of The Journal of Physiology, Hoedt and colleagues (Hoedt et al. 2016) sought to manipulate satellite cell behaviour in the vastus lateralis of healthy young men via two distinct but seemingly complementary strategies: chronic administration of a substance known to enhance aerobic exercise performance and a 10 week high-intensity interval (80–100% aerobic capacity) and continuous (70% aerobic capacity) cycling exercise training programme. The authors hypothesized that supplementation with an erythropoiesis-stimulating agent (ESA, darbepoetin-α, or synthetic erythropoietin that reportedly binds erythropoietin receptors) would enhance satellite cell myogenic commitment (i.e. MyoD+ indicating commitment to a myogenic/proliferative programme) and fibre type-specific density to an extent similar to that of aerobic training. In addition, the authors evaluated whether ESA treatment combined with aerobic exercise training resulted in a synergistic effect on satellite cell behaviour. Prior to this investigation, the evidence for whether erythropoietin could directly interact with satellite cells in humans was questionable based on methodological limitations. To address this, the investigators successfully employed an advanced cell sorting technique (fluorescent activated cell sorting, or FACS), rarely utilized in human muscle research, to isolate and better characterize satellite cells at the transcriptional level. The result from FACS revealed that purified satellite cells express receptors that can interact with erythropoietin, thereby forming a strong basis for the proposed hypotheses. The major findings of this investigation were: (1) ESA treatment and endurance training both increased satellite cell myogenic commitment, (2) there was no synergistic effect on satellite cell myogenic commitment between ESA treatment and endurance training, and (3) endurance training, regardless of ESA treatment, increased fast twitch-specific satellite cell density. A number of secreted substances, such as inflammatory-related cytokines and trophic factors, are known to modulate
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
satellite cell behaviour. Although serum erythropoietin/darbepoetin-α levels were not significantly elevated after 10 weeks of treatment, Hoedt et al. provide compelling evidence that erythropoietin (a hormone with both therapeutic and performance-enhancing potential) can increase the myogenic commitment of satellite cells. Interestingly, neither ESA treatment nor aerobic training resulted in increased myonuclei per fibre for any fibre type, suggesting an enhanced proliferative state did not ultimately translate to myonuclear accretion. Increasing the number of proliferating satellite cells seemingly serves a different purpose in human skeletal muscle remodelling. Moreover, increased whole body aerobic capacity (via ESA treatment) in the absence of exercise training was not sufficient to affect satellite cell density. It can be concluded that the mechanical loading, energetic perturbation, and/or overall systemic environment during exercise is a more potent stimulator of satellite cell accumulation than aerobic fitness level per se in humans. Increased fast twitch-specific satellite cell density with aerobic training reported by Hoedt et al. (2016) is in agreement with one study (Verney et al. 2008), but contrasts with two recent investigations (Joanisse et al. 2013; Fry et al. 2014). In elderly men (70–76 years), Verney et al. found that 14 weeks of interval cycling (75–95% heart rate maximum) increased fast twitch-specific satellite cell density. This occurred in conjunction with fast twitch-specific hypertrophy, but global myonuclear density did not increase (Verney et al. 2008). In a diverse group of subjects (men and women, 26–68 years), Fry et al. reported hypertrophy of all fibre types after 12 weeks of continuous submaximal cycle training (70% heart rate reserve), but satellite cell and myonuclear density only increased in slow twitch fibres (Fry et al. 2014). In response to 6 weeks of high-intensity interval cycling (90% heart rate maximum), Joanisse et al. reported that satellite cell density increased in co-expressing slow/fast ‘hybrid’ fibres in the absence of hypertrophy in young untrained women (Joanisse et al. 2013). However, similar to Hoedt et al., Joanisse et al. report a low average abundance of hybrid fibres before and after aerobic training (1–5%);
DOI: 10.1113/JP272746
5044 this could limit the reliability, interpretation and physiological relevance of hybrid fibre findings. Hoedt et al. did not report information on muscle fibre size in their investigation, and subject populations and training volumes/intensities across studies were variable. Moreover, Verney et al. employed NCAM as the satellite cell marker, which is not satellite cell specific, whereas Hoedt et al., Fry et al. and Joanisse et al. utilized PAX7, which is satellite cell specific. Further research utilizing more homogeneous subject cohorts, aerobic training stimuli, fibre size measures, and satellite cell markers is warranted to determine under what conditions satellite cell behaviour is fibre type specific. As the role(s) of satellite cells in muscle remodelling continue to be defined, establishing which substances can influence satellite cell behaviour in vivo can help guide human training programmes and therapeutics. Determining whether satellite cells have a fibre type-specific role in adaptation is also important since fibre type distribution can change considerably in response to exercise training, ageing, disuse and disease (to name a few). The work of Hoedt and colleagues provides noteworthy information on how a performanceenhancing and therapeutic substance affects satellite cell behaviour under resting
Journal Club conditions and in combination with exercise training. Moreover, the fibre type-specific satellite cell findings facilitate further conversation on how satellite cells contribute to adaptation in human skeletal muscle. References Fry CS, Lee JD, Mula J, Kirby TJ, Jackson JR, Liu F, Yang L, Mendias CL, Dupont-Versteegden EE, McCarthy JJ & Peterson CA (2015). Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat Med 21, 76–80. Fry CS, Noehren B, Mula J, Ubele MF, Westgate PM, Kern PA & Peterson CA (2014). Fibre type-specific satellite cell response to aerobic training in sedentary adults. J Physiol 592, 2625–2635. Hoedt A, Christensen B, Nellemann B, Mikkelsen UR, Hansen M, Schjerling P & Farup J (2016). Satellite cell response to erythropoietin treatment and endurance training in healthy young men. J Physiol 594, 727–743. Jackson JR, Kirby TJ, Fry CS, Cooper RL, McCarthy JJ, Peterson CA & Dupont-Versteegden EE (2015). Reduced voluntary running performance is associated with impaired coordination as a result of muscle satellite cell depletion in adult mice. Skelet Muscle 5, 41.
J Physiol 594.18
Joanisse S, Gillen JB, Bellamy LM, McKay BR, Tarnopolsky MA, Gibala MJ & Parise G (2013). Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. FASEB J 27, 4596–4605. Keefe AC, Lawson JA, Flygare SD, Fox ZD, Colasanto MP, Mathew SJ, Yandell M & Kardon G (2015). Muscle stem cells contribute to myofibres in sedentary adult mice. Nat Commun 6, 7087. McCarthy JJ, Mula J, Miyazaki M, Erfani R, Garrison K, Farooqui AB, Srikuea R, Lawson BA, Grimes B, Keller C, Van Zant G, Campbell KS, Esser KA, Dupont-Versteegden EE & Peterson CA (2011). Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development 138, 3657–3666. Verney J, Kadi F, Charifi N, Feasson L, Saafi MA, Castells J, Piehl-Aulin K & Denis C (2008). Effects of combined lower body endurance and upper body resistance training on the satellite cell pool in elderly subjects. Muscle Nerve 38, 1147–1154. Additional information Competing interests
None declared. Acknowledgements
The author wishes to thank Drs Charlotte Peterson and Vandr´e Casagrande Figueirido for their input on this manuscript.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
J Physiol 594.18 (2016) pp 5043–5044
JOURNAL CLUB
Delineating the effects of aerobic training versus aerobic capacity on satellite cell behaviour in humans Kevin A. Murach Center for Muscle Biology and Department of Rehabilitation Sciences, College of Health Sciences, University of Kentucky, Lexington, KY 40536, USA
The Journal of Physiology
Email: [email protected]
Since the initial characterization of muscle stem cells (satellite cells) in 1961, significant time and energy has been dedicated to uncovering their function in skeletal muscle. Over 50 years later, researchers are still elucidating the role(s) satellite cells play in exercise adaptation, ageing, health and disease. Satellite cells are indisputably necessary for regeneration (i.e. successful recovery from injury), but their requirement as myonuclear donors during adult skeletal muscle hypertrophy has been challenged using an inducible satellite cell knockout mouse (McCarthy et al. 2011). Depletion of satellite cells prior to endurance training in adult mice does not affect fibre type transitioning or muscle aerobic adaptations, but does affect coordination and running performance by disrupting intrafusal fibre (i.e. muscle spindle) morphology and activity (Jackson et al. 2015). Satellite cells play a homeostatic role by contributing to muscle fibres (Keefe et al. 2015) and regulating fibrosis (Fry et al. 2015) throughout the lifespan in sedentary mice, but do not appear to mediate sarcopenia with ageing (Fry et al. 2015; Keefe et al. 2015). Transgenic mouse models that permit post-developmental manipulation of satellite cells in conjunction with rodent muscle training techniques provide invaluable information on satellite cell biology and behaviour, but the question of translatability to humans is always pertinent. To that point, a multitude of human research indicates that satellite cell activity and density increases profoundly in response to varying environmental stimuli (e.g. exercise), strongly signifying an active role in the muscle adaptive process. Most recently, how satellite cells interact with secreted factors as well as their influence on muscle fibre type-specific adaptations
to exercise (e.g. slow versus fast twitch) has emerged as an area of inquiry in humans. In a recent issue of The Journal of Physiology, Hoedt and colleagues (Hoedt et al. 2016) sought to manipulate satellite cell behaviour in the vastus lateralis of healthy young men via two distinct but seemingly complementary strategies: chronic administration of a substance known to enhance aerobic exercise performance and a 10 week high-intensity interval (80–100% aerobic capacity) and continuous (70% aerobic capacity) cycling exercise training programme. The authors hypothesized that supplementation with an erythropoiesis-stimulating agent (ESA, darbepoetin-α, or synthetic erythropoietin that reportedly binds erythropoietin receptors) would enhance satellite cell myogenic commitment (i.e. MyoD+ indicating commitment to a myogenic/proliferative programme) and fibre type-specific density to an extent similar to that of aerobic training. In addition, the authors evaluated whether ESA treatment combined with aerobic exercise training resulted in a synergistic effect on satellite cell behaviour. Prior to this investigation, the evidence for whether erythropoietin could directly interact with satellite cells in humans was questionable based on methodological limitations. To address this, the investigators successfully employed an advanced cell sorting technique (fluorescent activated cell sorting, or FACS), rarely utilized in human muscle research, to isolate and better characterize satellite cells at the transcriptional level. The result from FACS revealed that purified satellite cells express receptors that can interact with erythropoietin, thereby forming a strong basis for the proposed hypotheses. The major findings of this investigation were: (1) ESA treatment and endurance training both increased satellite cell myogenic commitment, (2) there was no synergistic effect on satellite cell myogenic commitment between ESA treatment and endurance training, and (3) endurance training, regardless of ESA treatment, increased fast twitch-specific satellite cell density. A number of secreted substances, such as inflammatory-related cytokines and trophic factors, are known to modulate
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
satellite cell behaviour. Although serum erythropoietin/darbepoetin-α levels were not significantly elevated after 10 weeks of treatment, Hoedt et al. provide compelling evidence that erythropoietin (a hormone with both therapeutic and performance-enhancing potential) can increase the myogenic commitment of satellite cells. Interestingly, neither ESA treatment nor aerobic training resulted in increased myonuclei per fibre for any fibre type, suggesting an enhanced proliferative state did not ultimately translate to myonuclear accretion. Increasing the number of proliferating satellite cells seemingly serves a different purpose in human skeletal muscle remodelling. Moreover, increased whole body aerobic capacity (via ESA treatment) in the absence of exercise training was not sufficient to affect satellite cell density. It can be concluded that the mechanical loading, energetic perturbation, and/or overall systemic environment during exercise is a more potent stimulator of satellite cell accumulation than aerobic fitness level per se in humans. Increased fast twitch-specific satellite cell density with aerobic training reported by Hoedt et al. (2016) is in agreement with one study (Verney et al. 2008), but contrasts with two recent investigations (Joanisse et al. 2013; Fry et al. 2014). In elderly men (70–76 years), Verney et al. found that 14 weeks of interval cycling (75–95% heart rate maximum) increased fast twitch-specific satellite cell density. This occurred in conjunction with fast twitch-specific hypertrophy, but global myonuclear density did not increase (Verney et al. 2008). In a diverse group of subjects (men and women, 26–68 years), Fry et al. reported hypertrophy of all fibre types after 12 weeks of continuous submaximal cycle training (70% heart rate reserve), but satellite cell and myonuclear density only increased in slow twitch fibres (Fry et al. 2014). In response to 6 weeks of high-intensity interval cycling (90% heart rate maximum), Joanisse et al. reported that satellite cell density increased in co-expressing slow/fast ‘hybrid’ fibres in the absence of hypertrophy in young untrained women (Joanisse et al. 2013). However, similar to Hoedt et al., Joanisse et al. report a low average abundance of hybrid fibres before and after aerobic training (1–5%);
DOI: 10.1113/JP272746
5044 this could limit the reliability, interpretation and physiological relevance of hybrid fibre findings. Hoedt et al. did not report information on muscle fibre size in their investigation, and subject populations and training volumes/intensities across studies were variable. Moreover, Verney et al. employed NCAM as the satellite cell marker, which is not satellite cell specific, whereas Hoedt et al., Fry et al. and Joanisse et al. utilized PAX7, which is satellite cell specific. Further research utilizing more homogeneous subject cohorts, aerobic training stimuli, fibre size measures, and satellite cell markers is warranted to determine under what conditions satellite cell behaviour is fibre type specific. As the role(s) of satellite cells in muscle remodelling continue to be defined, establishing which substances can influence satellite cell behaviour in vivo can help guide human training programmes and therapeutics. Determining whether satellite cells have a fibre type-specific role in adaptation is also important since fibre type distribution can change considerably in response to exercise training, ageing, disuse and disease (to name a few). The work of Hoedt and colleagues provides noteworthy information on how a performanceenhancing and therapeutic substance affects satellite cell behaviour under resting
Journal Club conditions and in combination with exercise training. Moreover, the fibre type-specific satellite cell findings facilitate further conversation on how satellite cells contribute to adaptation in human skeletal muscle. References Fry CS, Lee JD, Mula J, Kirby TJ, Jackson JR, Liu F, Yang L, Mendias CL, Dupont-Versteegden EE, McCarthy JJ & Peterson CA (2015). Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat Med 21, 76–80. Fry CS, Noehren B, Mula J, Ubele MF, Westgate PM, Kern PA & Peterson CA (2014). Fibre type-specific satellite cell response to aerobic training in sedentary adults. J Physiol 592, 2625–2635. Hoedt A, Christensen B, Nellemann B, Mikkelsen UR, Hansen M, Schjerling P & Farup J (2016). Satellite cell response to erythropoietin treatment and endurance training in healthy young men. J Physiol 594, 727–743. Jackson JR, Kirby TJ, Fry CS, Cooper RL, McCarthy JJ, Peterson CA & Dupont-Versteegden EE (2015). Reduced voluntary running performance is associated with impaired coordination as a result of muscle satellite cell depletion in adult mice. Skelet Muscle 5, 41.
J Physiol 594.18
Joanisse S, Gillen JB, Bellamy LM, McKay BR, Tarnopolsky MA, Gibala MJ & Parise G (2013). Evidence for the contribution of muscle stem cells to nonhypertrophic skeletal muscle remodeling in humans. FASEB J 27, 4596–4605. Keefe AC, Lawson JA, Flygare SD, Fox ZD, Colasanto MP, Mathew SJ, Yandell M & Kardon G (2015). Muscle stem cells contribute to myofibres in sedentary adult mice. Nat Commun 6, 7087. McCarthy JJ, Mula J, Miyazaki M, Erfani R, Garrison K, Farooqui AB, Srikuea R, Lawson BA, Grimes B, Keller C, Van Zant G, Campbell KS, Esser KA, Dupont-Versteegden EE & Peterson CA (2011). Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. Development 138, 3657–3666. Verney J, Kadi F, Charifi N, Feasson L, Saafi MA, Castells J, Piehl-Aulin K & Denis C (2008). Effects of combined lower body endurance and upper body resistance training on the satellite cell pool in elderly subjects. Muscle Nerve 38, 1147–1154. Additional information Competing interests
None declared. Acknowledgements
The author wishes to thank Drs Charlotte Peterson and Vandr´e Casagrande Figueirido for their input on this manuscript.
C 2016 The Authors. The Journal of Physiology C 2016 The Physiological Society
