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Cell Death Dis ; 7: e2168, 2016 Mar 31.
Article in English | MEDLINE | ID: mdl-27031965

ABSTRACT

Although the mechanisms controlling skeletal muscle homeostasis have been identified, there is a lack of knowledge of the integrated dynamic processes occurring during myogenesis and their regulation. Here, metabolism, autophagy and differentiation were concomitantly analyzed in mouse muscle satellite cell (MSC)-derived myoblasts and their cross-talk addressed by drug and genetic manipulation. We show that increased mitochondrial biogenesis and activation of mammalian target of rapamycin complex 1 inactivation-independent basal autophagy characterize the conversion of myoblasts into myotubes. Notably, inhibition of autophagic flux halts cell fusion in the latest stages of differentiation and, conversely, when the fusion step of myocytes is impaired the biogenesis of autophagosomes is also impaired. By using myoblasts derived from p53 null mice, we show that in the absence of p53 glycolysis prevails and mitochondrial biogenesis is strongly impaired. P53 null myoblasts show defective terminal differentiation and attenuated basal autophagy when switched into differentiating culture conditions. In conclusion, we demonstrate that basal autophagy contributes to a correct execution of myogenesis and that physiological p53 activity is required for muscle homeostasis by regulating metabolism and by affecting autophagy and differentiation.


Subject(s)
Autophagy , Cell Differentiation , Mitochondria/metabolism , Myoblasts/cytology , Satellite Cells, Skeletal Muscle/cytology , Ammonium Chloride/pharmacology , Animals , Autophagy/drug effects , Beclin-1/antagonists & inhibitors , Beclin-1/genetics , Beclin-1/metabolism , Cell Differentiation/drug effects , Cells, Cultured , Leupeptins/pharmacology , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Knockout , Microscopy, Confocal , Microtubule-Associated Proteins/metabolism , Multiprotein Complexes/metabolism , Muscle Fibers, Skeletal/cytology , Muscle Fibers, Skeletal/metabolism , Myoblasts/metabolism , RNA Interference , RNA, Small Interfering/metabolism , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics
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