Today I'll point out a couple of recent papers that are illustrative of present research into muscle stem cells and the changes that take place in these cell populations with age. Note the interest in finding ways to modulate those changes, slow them down, or somewhat reverse them. Muscle stem cells are one of the most studied of stem cell populations, a state of affairs that is partly historical accident and partly because it is easier to obtain cells to work with that is the case for many other tissues. There are hundreds of cell types in the body, and every different form of tissue is supported by its own populations of stem cells and progenitor cells at various stages of differentiation. They are all very different, requiring different signals and circumstances in order to function correctly, as is illustrated by the fact that researchers need to develop new methodologies to work with each new tissue type that is built from cells in the laboratory. Understanding muscle stem cells is just one step on a lengthy road leading towards a complete catalog of the cellular biochemistry of tissue maintenance and regeneration.
All of our tissues are almost entirely composed of somatic cells with limited replicative lifespans. Once they reach the Hayflick limit, they self-destruct or become senescent, and most of the latter are destroyed by the
One of the most pressing aspects of stem cell biology is that the activity of stem cell populations decline with age, something that so far appears to be largely a matter of signaling when it comes to muscle stem cells. That may or may not universally true for other types of stem and progenitor cell. Certainly stem cell populations and their supporting niche cells suffer the molecular damage of aging just like other cells do. Nonetheless, in the case of muscle stem cells there are numerous studies demonstrating restored stem cell activity in old animals via various forms of intervention. Thus there is considerable interest in the research community when it comes to building a map of the biochemistry of this stem cell decline, and then building therapies to put these stem cells back to work. Loss of muscle mass and strength, and ability to regenerate from injury, is an important component of age-related frailty. If that can be reduced by overriding the reactions of cells to rising levels of damage, and without significantly raising the risk of cancer, then perhaps some good can be done here even in advance of methods of repairing the underlying damage that causes aging. I'd much rather see more work on rejuvenation through repair rather than forcing damaged cells into youthful patterns of behavior, but the latter is clearly going to happen regardless of my opinions on the matter: a fair number of research teams are headed in that direction. Stem cell research as a whole is set on a collision course with the issue of stem cell decline in aging, as a sizable majority of the therapies one would want to want to build using stem cell research are for age-related conditions. Solving the issues of failing stem cells in an old tissue environment must happen at some point in order for researchers to achieve their goals.
Satellite cells (SC) are adult muscle stem cells located at the periphery of muscle fibers. SCs are accordingly exposed to various signals from within and outside of the fiber, which collectively comprise the specific environment termed the SC niche. Although metabolically inactive and quiescent in resting conditions, SCs quickly become activated in response to a stimulus such as injury or strenuous exercise. These stem cells are indispensable for skeletal muscle regeneration, and despite being present in relatively small numbers (2-5% of total myonuclei), SCs have a vast proliferative and regenerative potential. Proper activation and proliferation, as well as return to quiescence, are all essential to preserving SC number and function. In various pathological contexts, for example, in certain muscular dystrophies or aging, a depletion of SC numbers is linked to impaired regenerative capacity. Importantly, reduced SC numbers and myogenic activity are often caused by alterations of the SC niche. For example, excess fibronectin in the basal lamina in an uninjured state is correlated with a reduced ability of SCs to respond to injury. Age-associated accumulation of extracellular matrix (ECM) components leads to the thickening of the basal lamina, thereby preventing SCs from sensing changes in the environment and resulting in a reduced activation propensity. Inversely, treatment with fibronectin can restore satellite cell activation in old muscle. Moreover, local transient fibronectin secretion by SCs is an important step in the cascade of SC activation and subsequent proliferation, and such a transient increase in fibronectin muscle expression is necessary for successful regeneration.
SC numbers vary by muscle fiber type, with higher counts present in oxidative compared to glycolytic muscle beds. In line with this, endurance exercise increases SC numbers in mice and humans. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a major driver of oxidative fiber-type specification, mitochondrial biogenesis, and high endurance capacity. Furthermore, PGC-1α gene expression is induced by exercise and exhibits a preference for slow, oxidative fibers. Finally, muscle-specific overexpression of PGC-1α protects against a variety of muscle-wasting conditions, including fiber atrophy or the pathologies in dystrophic mouse models. Nevertheless, a potential link between PGC-1α, oxidative fibers, exercise, and SCs has not been studied yet. By using a mouse model which specifically overexpresses PGC-1α in adult muscle fibers, we attempted to delineate the aforementioned missing link and assess the importance of indirect effects of PGC-1α on SC phenotype. Here, we show that muscle fiber PGC-1α modulates SC number as well as proliferation and that the latter, at least in part, could be regulated by the altered expression of ECM components, including fibronectin protein levels, in the basal lamina. Increased PGC-1α content in the SC niche therefore results in an accelerated SC response to injury and higher myogenic capacity.
During aging, myofiber size progressively decreases with an accompanying loss of fast twitch myofibers, leading to reduced overall muscle mass and strength that, when severe, results in sarcopenia. Loss of muscle mass and strength is accompanied by increased matrix deposition (fibrosis) and increased fat infiltration. Skeletal muscle regeneration is impaired in aged muscle and associated with cell-intrinsic deficits in satellite cell function; however, satellite cell contribution to sarcopenia has been recently questioned, although a contribution of satellite cell loss to aging-associated fibrosis is supported.
Satellite cells in G0 phase reside within the musculature and are poised to rapidly activate in response to injury. Upon activation, satellite cells re-enter the cell cycle, migrate away from their niche, and proliferate as myoblasts, eventually undergoing terminal differentiation into myocytes that fuse into pre-existing damaged muscle fibers or fuse to one another generating new muscle fibers. During regeneration, a portion of satellite cells returns to its niche, re-enters quiescence, and expresses Pax7 but no other myogenic transcription factors. The transmembrane heparan sulfate proteoglycan syndecan-3, a component of the satellite cell niche, controls satellite cell homeostasis by regulating signaling pathways within the niche. Moreover, members of the Syndecan family regulate cell-cell adhesion and cell-matrix adhesion via interaction with integrins and cadherins. Following a muscle injury, syndecan-3 null (Sdc3-/-) satellite cells fail to replenish the resident pool of quiescent satellite cells within the niche and therefore syndecan-3 appears to regulate satellite cell homeostasis.
We show that syndecan-3 loss alters satellite cell adhesion to the myofiber, altering interactions with the niche and (i) improves muscle regeneration upon repeated acute muscle injuries, (ii) rescues muscle histopathology and function in dystrophic muscle tissue, and (iii) improves muscle aging with a reduction in fibrosis. The lifelong improvement in muscle regeneration observed in Sdc3-/- muscle arises in part by altered satellite cell homeostasis and changes in satellite cell adhesiveness to the myofiber.