Mechanisms regulating skeletal muscle satellite cell cycle progression

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Skeletal muscle fibers are multinucleated with each myonucleus capable of governing a finite cytoplasmic volume. In healthy skeletal muscle, myonuclear number decreases with muscle atrophy and fiber damage and increases with hypertrophy, to maintain a constant myonuclear to cytoplasmic ratio. Myonuclei are post-mitotic, therefore, the repair, regrowth, and hypertrophy of skeletal muscle relies on satellite cells, muscle precursor cells located between the basal lamina and plasmalemma of mature muscle fibers. Since decreased satellite cell proliferation may limit the regrowth of old skeletal muscle following atrophy or damage, it is important to understand the mechanisms that control satellite cell proliferation to enable the development of countermeasures to treat muscle atrophy that occurs with age. Adenoviral infection of primary satellite cells with the forkhead transcription factor FoxO3a decreased satellite cell cycle progression; this process occurred, in part, through increases in the promoter activity and protein levels of the cyclin dependent kinase (cdk) inhibitor p27superscript Kip1], without altering p21[superscript Waf/Cip1] or cyclin D1 -CDK 4/6 activity. Conversely, increases in satellite cell cycle progression following adenoviral infection of Sirt1 were associated with a decrease in the cyclin dependent kinase inhibitor p21[superscript Waf/Cip1], increased p27[superscript Kip1], and increased cyclin D1 -CDK4/6 activity. In summary, it is speculated that these studies suggest that increasing FoxO3a expression alters factors that would decrease cell cycle progression of primary satellite cells, and this inhibition is likely through the inhibition of cyclin E -CDK2 and/or cyclin A -CDK2 activities via increases in p27[superscript Kip1]. Also, increasing the expression of Sirt1 increases satellite cell cell cycle progression by decreasing the expression levels of p21[superscript Waf/Cip1]. These studies are important for the understanding of the mechanisms that regulate satellite cell proliferation, more specifically, these studies have contributed to the understanding of two molecules that control satellite cell proliferation, FoxO3a and Sirt1.