Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation

Boa Kim, Ji Seok Kim, Yisang Yoon, Mayra C. Santiago, Michael D. Brown, Joon Young Park

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Mitochondria are dynamic organelles forming a tubular network that is continuously fusing and dividing to control their morphology and functions. Recent literature has shed new light on a potential link between the dynamic behavior of mitochondria and muscle development. In this study, we investigate the role of mitochondrial fission factor dynamin-related protein 1 (Drp1) in myogenic differentiation. We found that differentiation of C2C12 myoblasts induced by serum starvation was accompanied by a gradual increase in Drp1 protein expression (to ~350% up to 3 days) and a fast reduction of Drp1 phosphorylation at Ser-637 (to ~30%) resulting in translocation of Drp1 protein from the cytosol to mitochondria. During differentiation, treatment of myoblasts with mitochondrial division inhibitor (mdivi-1), a specific inhibitor of Drp1 GTPase activity, caused extensive formation of elongated mitochondria, which coincided with increased apoptosis evidenced by both enhanced caspase-3 activity and increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells. Furthermore, the mdivi-1 -treated myotubes (day 3 in differentiation media) showed a reduction in mitochondrial DNA content, mitochondrial mass, and membrane potential in a dose-dependent manner indicating defects in mitochondrial biogenesis during myogenic differentiation. Most interestingly, mdivi-1 treatment significantly suppressed myotube formation in both C2C12 cells and primary myoblasts. Likewise, stable overexpression of a dominant negative mutant Drp1 (K38A) dramatically reduced myogenic differentiation. These data suggest that Drp-1-dependent mitochondrial division is a necessary step for successful myogenic differentiation, and perturbation of mitochondrial dynamics hinders normal mitochondrial adaptations during muscle development. Therefore, in the present study, we report a novel physiological role of mitochondrial dynamics in myogenic differentiation.

Original languageEnglish (US)
Pages (from-to)R927-R938
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume305
Issue number8
DOIs
StatePublished - Oct 15 2013

Keywords

  • Dynamin-related protein 1
  • Mdivi-1
  • Mitochondrial dynamics
  • Myogenesis

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Inhibition of Drp1-dependent mitochondrial division impairs myogenic differentiation'. Together they form a unique fingerprint.

  • Cite this