title: Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts.
abstract: Myogenesis is a crucial process governing skeletal muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNM1L/DRP1 (dynamin 1-like)-mediated fragmentation and subsequent removal of mitochondria via SQSTM1 (sequestosome 1)-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α (peroxisome proliferator-activated receptor gamma, coactivator 1 alpha)-mediated biogenesis. Mitochondrial fusion protein OPA1 (optic atrophy 1 [autosomal dominant]) is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that suppressing autophagy with various inhibitors during differentiation interferes with myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Sin
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: Allen M
authors.initials: AM
authors.lastname: Andres
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: David J R
authors.initials: DJ
authors.lastname: Taylor
authors.affiliation: b Department of Biology , San Diego State University , San Diego , CA , USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weston
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hiraumi
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Stotland
authors.affiliation: b Department of Biology , San Diego State University , San Diego , CA , USA.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: Chengqun
authors.initials: C
authors.lastname: Huang
authors.affiliation: b Department of Biology , San Diego State University , San Diego , CA , USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Doran
authors.affiliation: a The Cedars-Sinai Heart Institute and the Barbra Streisand Women's Heart Center Cedars-Sinai Medical Center , Los Angeles , CA , USA.
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063306:Mitophagy / Q000187:drug effects; D008954:Models, Biological; D024510:Muscle Development / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D001678:Organelle Biogenesis; D010085:Oxidative Phosphorylation / Q000187:drug effects
chemical_list: D018942:Macrolides; C040929:bafilomycin A1
keywords: autophagy; differentiation; mitochondria; mitophagy; myoblasts; myogenesis; myotubes