Satellite cells: promoting adaptation over a lifetime

The article by Mackey et al. titled ‘Differential regulation of the satellite cell density of type I and type II fibres with lifelong endurance running in old men’ touches on several pertinent points regarding satellite cells and ageing. The authors report that lifelong endurance training in an older adult population did not deplete the satellite cell pool. Furthermore, the fibre-type satellite cell distribution data demonstrated that in older vs. younger adults, there were fewer satellite cells associated with type II fibres as compared to type I fibres in both trained and untrained groups. Interestingly, when satellite cell content relative to fibre area was taken into consideration, both the older and younger adult trained groups demonstrated an equal distribution of satellite cells between fibre types, while the untrained group demonstrated a lower density of satellite cells in the type II fibres. A primary contribution of this work is the inclusion of older lifelong endurance runners. Collecting data in lifelong exercisers who have averaged almost 50 km of running per week for almost 30 years is a methodological and logistical challenge. The field of satellite cell regulation with exercise is dominated by investigations applying acute exercise protocols and short-term training programmes, and the results of these types of studies are liberally extrapolated with the assumption that acute responses to exercise will then reflect what we could expect over a lifetime of exercise. This, of course is only a hope, and studies such as the one appearing in this issue make invaluable contributions to our field. The current study also goes a step further, contributing hard data to two ‘hot’ debates in satellite cell biology. First, it debunks a theory based on an in vitro observation made many years ago. In the early 1960s, the term ‘Hayflick phenomenon’ was coined and described the notion that human cells possess a finite capacity for cell division. The limit on the number of cell divisions was seen as primarily dictated by the shortening of telomeres with each division until the point of replicative senescence (Hayflick & Moorhead 1961). Although the Hayflick phenomenon is an event mostly restricted to in vitro observations, there are in vivo examples of satellite cell exhaustion in conditions such as muscular dystrophy (Renault et al. 2000, Thornell et al. 2009). Muscular dystrophy is characterized by cycles of degeneration and subsequent regeneration achieved through normal satellite cell function. It is thought that this process leads to a more rapid rate of telomere shortening and ultimate loss of the satellite cell pool, presumably through the principles underlying the Hayflick phenomenon. The question has been raised, usually by those less familiar with our field, whether lifelong exercise may lead to exhaustion of the satellite cell pool and ultimately contribute to age-related loss of skeletal muscle and function. Indeed, a loss in satellite cell pool size has been described as a function of ageing (Verdijk et al. 2013). More interestingly, age-related contraction of satellite cell pool size appears to happen in a fibre-type-specific fashion with type II fibres selectively losing satellite cells compared with type I fibres. The reason behind this fibre-type-specific attrition of satellite cells is still being debated, and to date, little has been done to explore the mechanisms underlying this observation. The present study by Mackey et al. deflates the assumption that chronic exercise over a lifetime can lead to exhaustion of the satellite cell pool. They demonstrate the clear maintenance of the satellite cell pool in older adults who had engaged in regular exercise for almost 30 years. It is worth noting that Mackey et al. do not describe a reduction in the satellite cell pool as a function of age, and some may see this as a limitation or even suggest that one cannot conclude that chronic exercise maintained pool size when there was not an age-related contraction in the aged control group. The reality is that this phenomenon is likely explained by the relatively ‘young’ and healthy older adult control group recruited for this study. Although the loss of satellite cells is progressive from early adulthood, the most appreciable changes are not truly observed until the late 7th or early 8th decade of life (Verdijk et al. 2013). Another recent hot issue in the field of satellite cell biology concerns the precise role of satellite cells in skeletal muscle. Some have suggested that satellite cells are not necessary for growth. Based on animal models, this might be considered absolutely true (McCarthy et al. 2011). However, in almost every human study involving resistance training-induced skeletal muscle growth, a significant increase in the number of myonuclei per muscle fibre has been reported (Kadi et al. 1999, Eriksson et al. 2005, Petrella et al. 2008), suggesting a contribution of satellite cells to growth. Furthermore, those with the greatest capacity for exercise-induced muscle growth were the same individuals who possessed the greatest satellite cell pool size before training and the same individuals who realized the greatest expansion of the satellite cell pool after training (Petrella et al. 2008, Verdijk et al. 2013). The theory that satellite cells contribute to muscle growth is again supported by the data presented by Mackey et al. In this study, they demonstrate a rather strong association between satellite cell number and fibre size in both their young and older adult trained groups. Interestingly, this relationship was not evident in the old untrained group and was much weaker in the untrained young adults. It may be that the exercise stimulus, whether in younger or older adults, induced an increased contribution of nuclei to existing muscle fibres to promote adaption including growth. More interesting perhaps is that it has been well documented that ‘health’ and presumably ‘muscle health’ are significantly improved with regular exercise in older adults. Indeed, older adult runners show a reduced incidence of morbidity and mortality (Chakravarty et al. 2008), and this is generally in the absence of skeletal muscle hypertrophy indicating that growth and muscle size, per se, are only one consideration in determining one's muscle health in older adulthood. Mackey et al. report no significant differences in skeletal muscle fibre size between trained and untrained groups, yet we know from previous reports that endurance-type exercise can indeed stimulate activation and expansion of the satellite cell pool (Charifi et al. 2003). This raises the question: Is there a benefit to promoting nuclear turnover through satellite cell contribution with exercise? This question was not addressed in the current study but the lack of fibre hypertrophy in these subjects engaging in chronic exercise known to stimulate a satellite cell response and who are undoubtedly healthier as a result of logging on average 48 km per week for the past 30 years may lead one to believe that turning over nuclei in skeletal muscle in and of itself may promote healthier skeletal muscle. Admittedly, this issue remains completely unexplored. Nuclear turnover as a concept has not been readily accepted as common dogma, primarily due to discrepant findings using animal models and the fact that the concept of nuclear turnover in skeletal muscle is not easily interrogated in human muscle. In 2013, my group published a paper demonstrating evidence of satellite cell contribution to human skeletal muscle in the absence of skeletal muscle hypertrophy (Joanisse et al. 2013). It appeared that muscle fibres undergoing remodelling (based on the presence of central nuclei, co-expression of MHC and or expression of neonatal MHC) were associated with a larger pool of satellite cells. More importantly, more of the satellite cells in association with these fibres were active as determined through the co-localization of myoD. Satellite cell contribution to skeletal muscle may not be about promoting growth, but may be about promoting an adapted environment, which may or may not include growth. In the study of Mackey et al., there was no evidence of muscle fibre hypertrophy in the chronic exercisers over and above that of the control group. Satellite cells may play a role in promoting a healthier muscle environment and preserving the satellite cell response as we age may be critical for skeletal muscle health. The study by Mackey et al. offers many interesting findings, all of which is not possible to highlight here. Using lifelong exercisers to try to fully understand the health benefits of exercise and understand the efficacy of exercise to delay or diminish the adverse effects of ageing is invaluable. The data collected by Mackey et al. provide insights into the benefits of regular exercise throughout the life span, and in the process, also provide insight into two hot button issues in satellite cell biology. None.

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