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Mitochondrial dynamics define muscle fiber type by modulating cellular metabolic pathways.

Tatsuki Yasuda1, Takaya Ishihara2, Ayaka Ichimura3

  • 1Department of Biological Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.

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Mitochondrial fission, regulated by dynamin-related protein 1 (Drp1), is crucial for fast-twitch muscle fiber development. Its depletion activates the Akt/mTOR pathway, hindering fiber differentiation.

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AktCP: MetabolismDrp1GDF-15mTORmitochondriamitochondrial dynamicsmuscle atrophymuscle differentiation

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Area of Science:

  • Cell Biology
  • Muscle Physiology
  • Mitochondrial Dynamics

Background:

  • Skeletal muscle comprises fast-twitch and slow-twitch fibers, but fiber-type differentiation mechanisms remain unclear.
  • Mitochondrial dynamics, including fission and fusion, play vital roles in cellular functions.

Purpose of the Study:

  • To investigate the role of mitochondrial fission in skeletal muscle fiber-type differentiation.
  • To elucidate the molecular mechanisms linking mitochondrial fission to fast-twitch fiber development.

Main Methods:

  • Utilized mouse models with depleted dynamin-related protein 1 (Drp1) in skeletal muscle.
  • Employed cultured myotubes to study mitochondrial fission and its effects.
  • Analyzed the involvement of the Akt/mammalian target of rapamycin (mTOR) pathway and growth differentiation factor 15 (GDF15).

Main Results:

  • Depletion of Drp1 specifically reduced fast-twitch muscle fibers, independent of respiratory function.
  • Altered mitochondrial fission led to mTOR complex 2 (mTORC2) accumulation on mitochondria, activating the Akt/mTOR pathway.
  • Rapamycin treatment rescued the reduction of fast-twitch fibers in vivo and in vitro.
  • Akt/mTOR activation upregulated GDF15, which inhibited fast-twitch fiber differentiation.

Conclusions:

  • Mitochondrial fission is essential for the differentiation of fast-twitch skeletal muscle fibers.
  • Mitochondrial dynamics regulate Akt/mTORC2 signaling, impacting muscle fiber development.
  • Targeting mitochondrial dynamics or the Akt/mTOR pathway may offer therapeutic strategies for muscle disorders.