The ins and outs of muscle stem cell aging

Abstract

Skeletal muscle has a remarkable capacity to regenerate by virtue of its resident stem cells (satellite cells). This capacity declines with aging, although whether this is due to extrinsic changes in the environment and/or to cell-intrinsic mechanisms associated to aging has been a matter of intense debate. Furthermore, while some groups support that satellite cell aging is reversible by a youthful environment, others support cell-autonomous irreversible changes, even in the presence of youthful factors. Indeed, whereas the parabiosis paradigm has unveiled the environment as responsible for the satellite cell functional decline, satellite cell transplantation studies support cell-intrinsic deficits with aging. In this review, we try to shed light on the potential causes underlying these discrepancies. We propose that the experimental paradigm used to interrogate intrinsic and extrinsic regulation of stem cell function may be a part of the problem. The assays deployed are not equivalent and may overburden specific cellular regulatory processes and thus probe different aspects of satellite cell properties. Finally, distinct subsets of satellite cells may be under different modes of molecular control and mobilized preferentially in one paradigm than in the other. A better understanding of how satellite cells molecularly adapt during aging and their context-dependent deployment during injury and transplantation will lead to the development of efficacious compensating strategies that maintain stem cell fitness and tissue homeostasis throughout life.

Conditional Loss of Pten in Myogenic Progenitors Leads to Postnatal Skeletal Muscle Hypertrophy but Age-Dependent Exhaustion of Satellite Cells

“…This observation indicates that G Alert satellite cells have a shorter lifespan. Age-related depletion of stem cell pool mainly results from deregulated stem cell homeostasis due to the loss of self-renewal ability and activation of senescence pathways (Brack and Muñoz-Cánoves, 2016; Chakkalakal et al, 2012; Liu and Rando, 2011; Signer and Morrison, 2013; Sousa-Victor et al, 2015). Indeed, we find that G Alert satellite cells have reduced self-renewal ability.…”

“…As Pten function as an antagonist of the IGF signaling, these studies together highlight the role of inhibitors of growth factor signaling pathways in stem cell maintenance. Intrinsic molecular effectors such as Spry1, Pten and p38αβ/MAPK may function as mediators of extrinsic signaling to control satellite cell homeostasis (Bernet et al, 2014; Brack and Muñoz-Cánoves, 2016; Chakkalakal et al, 2012; Shea et al, 2010). …”

“…During aging, the regenerative capacity of skeletal muscle declines due to functional declination of systemic environment and satellite cells (Blau et al, 2015). Many intrinsic and extrinsic signals have been shown to govern the function of satellite cells, including Notch, Wnt, p38/MAPK, JNK/STAT, FGF and many others (Almada and Wagers, 2016; Blau et al, 2015; Brack and Muñoz-Cánoves, 2016; Dumont et al, 2015). …”

Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

“…Novel therapeutics to restore skeletal muscle repair mechanisms could improve the quality of life in old individuals. 41 …”

Altered satellite cell dynamics accompany skeletal muscle atrophy during chronic illness, disuse, and aging

“…Several recent review articles provide in-depth assessment of cell-intrinsic and -extrinsic modifications to satellite cells that contribute to their functional decline with advancing age (25–27). Age-related declines in satellite cell abundance have also been well-documented in rodents (28*) and humans (29); as such, satellite cells remain a popular therapeutic target in the management of sarcopenia.…”