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Tetrandrine Inhibits Skeletal Muscle Differentiation by Blocking Autophagic Flux

Jing Li1, Meiyun Shi1, Lutao Liu1

  • 1Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, China.

International Journal of Molecular Sciences
|July 28, 2022
PubMed

Insights

Tetrandrine, a potential cancer drug, inhibits skeletal muscle differentiation by blocking autophagic flux and disrupting mitochondria. This finding suggests caution for its use in cancer patients with muscle complications.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Muscle Physiology

Background:

  • Tetrandrine is a calcium channel blocker investigated for cancer chemotherapy.
  • Cancer patients often suffer from sarcopenia and muscle injury.
  • The effects of tetrandrine on skeletal muscle cells remain largely unexplored.

Purpose of the Study:

  • To investigate the impact of tetrandrine on skeletal muscle cells, specifically C2C12 myoblasts.
  • To elucidate the underlying mechanisms of tetrandrine's effects on myogenic differentiation and muscle regeneration.

Main Methods:

  • Treatment of C2C12 myoblasts with varying doses of tetrandrine.
  • Assessment of myogenic differentiation and muscle regeneration after barium chloride-induced injury.
  • Analysis of autophagic flux using Ad-mRFP-GFP-LC3B transfection.
  • Evaluation of mitochondrial signaling pathways, including mTOR, LC3, SQSTM1/p62, DNM1L/Drp1, PPARGA1, cytochrome c, caspase 3 activation, and ROS production.

Main Results:

  • Low-dose tetrandrine ( < 5 μM) inhibited myogenic differentiation and muscle regeneration without affecting myoblast proliferation.
  • Tetrandrine exhibited dual effects on autophagic flux, activating it early and blocking it late during differentiation.
  • The drug disrupted mitochondrial remodeling by inhibiting mitochondrial network signaling and suppressing autophagic flux.
  • Tetrandrine decreased p-mTOR, increased LC3 and SQSTM1/p62, suppressed lysosomal GFP quenching, and reduced levels of DNM1L/Drp1, PPARGA1, and cytochrome c.

Conclusions:

  • Tetrandrine blocks autophagic flux in the late stage of myoblast differentiation, leading to impaired mitochondrial remodeling and inhibited myogenic differentiation.
  • The inhibitory effects of tetrandrine on skeletal muscle differentiation may limit its clinical application in advanced cancer patients.
  • Careful consideration is required for the clinical use of tetrandrine in cancer therapy due to its potential impact on skeletal muscle health.
Keywords:
autophagymitochondriamyoblastmyogenic differentiationtetrandrine

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