The fine tuning of metabolism, autophagy and differentiation during in vitro myogenesis

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 satelli...

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Published in:	Cell death & disease Vol. 7; no. 3; p. e2168
Main Authors:	Fortini, P, Ferretti, C, Iorio, E, Cagnin, M, Garribba, L, Pietraforte, D, Falchi, M, Pascucci, B, Baccarini, S, Morani, F, Phadngam, S, De Luca, G, Isidoro, C, Dogliotti, E
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 31-03-2016 Springer Nature B.V Nature Publishing Group
Subjects:	13 14/1 14/63 38 631/136/142 631/136/1660 631/443/319 631/80/82/39 Ammonium Chloride - pharmacology Animals Antibodies Autophagy Autophagy - drug effects Beclin-1 - antagonists & inhibitors Beclin-1 - genetics Beclin-1 - metabolism Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell Differentiation - drug effects Cells, Cultured Gene expression Immunology Leupeptins - pharmacology Life Sciences Mechanistic Target of Rapamycin Complex 1 Metabolism Mice Mice, Knockout Microscopy, Confocal Microtubule-Associated Proteins - metabolism Mitochondria - metabolism Multiprotein Complexes - metabolism Muscle Fibers, Skeletal - cytology Muscle Fibers, Skeletal - metabolism Musculoskeletal system Myoblasts - cytology Myoblasts - metabolism Myogenesis Original original-article RNA Interference RNA, Small Interfering - metabolism Satellite Cells, Skeletal Muscle - cytology TOR Serine-Threonine Kinases - metabolism Tumor Suppressor Protein p53 - deficiency Tumor Suppressor Protein p53 - genetics
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/cddis.2016.50