Adult skeletal muscle has a remarkable ability to regenerate following myotrauma. Because adult myofibers are terminally differentiated, the regeneration of skeletal muscle is largely dependent on a small population of resident cells termed satellite cells. Although this population of cells was identified 40 years ago, little is known regarding the molecular phenotype or regulation of the satellite cell. The use of cell culture techniques and transgenic animal models has improved our understanding of this unique cell population; however, the capacity and potential of these cells remain ill-defined. This review will highlight the origin and unique markers of the satellite cell population, the regulation by growth factors, and the response to physiological and pathological stimuli. We conclude by highlighting the potential therapeutic uses of satellite cells and identifying future research goals for the study of satellite cell biology.

Myogenic satellite cells: physiology to molecular biology.

Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process invol...

Satellite Cells and the Muscle Stem Cell Niche

Rapamycin, a macrocyclic lactone, is a highly specific inhibitor of the serine/threonine protein kinase target of rapamycin (TOR). Although it is clear that TOR controls initiation of protein translation, recent results indicate that TOR is a central controller, integrating a plethora of signalling pathways that respond to growth factors and nutritional status. In addition to the role of rapamycin as an immune suppressant, emerging data indicate that genetic and metabolic changes accompanying malignant transformation might cause hypersensitivity to TOR inhibition.

The tor pathway: a target for cancer therapy

Extracellular signals often result in simultaneous activation of both the Raf-MEK-ERK and PI3K-Akt pathways (where ERK is extracellular-regulated kinase, MEK is mitogen-activated protein kinase or ERK kinase, and PI3K is phosphatidylinositol 3-kinase). However, these two signaling pathways were shown to exert opposing effects on muscle cell hypertrophy. Furthermore, the PI3K-Akt pathway was shown to inhibit the Raf-MEK-ERK pathway; this cross-regulation depended on the differentiation state of the cell: Akt activation inhibited the Raf-MEK-ERK pathway in differentiated myotubes, but not in their myoblast precursors. The stage-specific inhibitory action of Akt correlated with its stage-specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.

https://science.sciencemag.org/content/sci/286/5445/1738.full.pdf

Differentiation Stage-Specific Inhibition of the Raf-MEK-ERK Pathway by Akt

The Mitogenic and Myogenic Actions of Insulin-like Growth Factors Utilize Distinct Signaling Pathways

Mitogens are generally thought to inhibit myogenesis, and many cell biologists have found it hard to interpret observations that the insulin-like growth factors (IGFs) stimulate both proliferation and differentiation of muscle cells in culture. Our previous studies suggested that the Type I IGF receptor mediates these actions. However, IGF-II and insulin treatment caused myoblasts to differentiate much more extensively, suggesting that more complex mechanisms may be involved. Here we present evidence that the greater mitogenic activity of IGF-I (compared to IGF-II and insulin) delays L6A1 myoblast differentiation. Under conditions in which the mitogenic actions of IGF-I are suppressed, the stimulation of myogenesis by IGF-I approached that by IGF-II: (1) in L6A1 cultures plated at a higher cell density; (2) in L6A1 cultures in which cell proliferation was inhibited by cytosine arabinoside or aphidicolin; and (3) in cultures of primary human muscle cells, which exhibit a smaller mitogenic response to IGF-I. Further evidence that the Type I receptor plays a major role in relaying the signal for differentiation was obtained by using IGF-I and IGF-II analogs. Analogs which have reduced affinity for the Type I receptor showed a dramatic decrease in activity, while an analog with increased affinity for the Type II receptor was no more active than native IGF-I. Our results indicate that both mitogenic and myogenic actions of IGF-I are mediated by the Type I receptor. We conclude that IGF-I delays the onset of myogenesis as a result of its mitogenic actions, and only subsequently stimulates myogenesis. These observations reconcile the apparent conflict between our results with the IGFs and other investigators' reports of effects of other mitogens.

Frank J. McWade

Papers

The Mitogenic and Myogenic Actions of Insulin-like Growth Factors Utilize Distinct Signaling Pathways

IGF-II is more active than IGF-I in stimulating L6A1 myogenesis: greater mitogenic actions of IGF-I delay differentiation