Abstract
Regeneration of muscle fibers, lost during pathological muscle degeneration or after injuries, is sustained by the production of new myofibers by means of the satellite cells. Survival of the satellite cells is a critical requirement for efficient muscle reconstitution. Necdin, a member of the MAGE proteins family, is expressed in satellite cell-derived myogenic precursors during perinatal growth and in the adult upon activation during muscle regeneration, where it plays an important role both in myoblast differentiation and survival. We show here that necdin exerts its pro-survival activity by counteracting the action of the pro-apoptotic protein Cell Cycle Apoptosis Regulatory Protein (CCAR1/CARP1) that we have identified as a new molecular interactor of necdin by two-hybrid screening. Necdin is responsible for the maintenance of CCAR1 protein levels, by implementing its ubiquitination and degradation through the proteasome. Taken together, these data shed new light on the molecular mechanism of necdin anti-apoptotic activity in myogenesis.
Highlights
Skeletal muscle tissue is characterized by a very slow turnover that accelerates upon certain physiological stimuli or in pathological conditions, such as primary myopathies, leading to an extensive repair process aimed at preventing the loss of muscle mass
We have demonstrated that necdin is a critical player in sustaining survival of satellite cells and other myogenic stem cells such as the mesoangioblasts [12,16]
We show that it physically interacts with a protein that plays an important role in regulating cell death, Cell Cycle and Apoptosis Regulatory protein-1 (CCAR1/CARP1) [19,20,22] and counteracts its pro-apoptotic effect
Summary
Skeletal muscle tissue is characterized by a very slow turnover that accelerates upon certain physiological stimuli or in pathological conditions, such as primary myopathies, leading to an extensive repair process aimed at preventing the loss of muscle mass. Sprouty (Spry1), a receptor tyrosine kinase signalling inhibitor, is required to maintain the quiescent stem cell pool during muscle repair [10]. It is expressed in quiescent satellite cells, downregulated in proliferating myogenic cells after injury, and re-induced as cells re-enter quiescence. In absence of Spry function, regenerating muscles show increased number of apoptotic myogenic cells [10] Other pleiotropic signals, such as the Ang1/Tie system, promote satellite cell survival, and contribute to the regulation of stem cell quiescence and self-renewal in skeletal muscle [11]
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