Pharmacological inhibition of dynamin-related protein 1 attenuates skeletal muscle insulin resistance in obesity

Physiol Rep. 2021 Apr;9(7):e14808. doi: 10.14814/phy2.14808.

Abstract

Dynamin-related protein-1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1-mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1-specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi-1), is effective in alleviating skeletal muscle insulin resistance and improving whole-body metabolic health under the obese and insulin-resistant condition. We subjected C57BL/6J mice to a high-fat diet (HFD) or low-fat diet (LFD) for 5-weeks. HFD-fed mice received Mdivi-1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin-resistant humans were treated with Mdivi-1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H2 O2 content. We found that Mdivi-1 attenuated impairments in skeletal muscle insulin signaling and blood glucose AUC from a GTT induced by HFD feeding (p < 0.05). H2 O2 content was elevated in skeletal muscle from the HFD group (vs. LFD, p < 0.05), but was reduced with Mdivi-1 treatment, which may partially explain the improvement in skeletal muscle insulin action. Similarly, Mdivi-1 enhanced the mitochondrial network structure, reduced reactive oxygen species, and improved insulin action in myotubes from obese humans (vs. saline, p < 0.05). In conclusion, inhibiting Drp1 with short-term Mdivi-1 administration attenuates the impairment in skeletal muscle insulin signaling and improves whole-body glucose tolerance in the setting of obesity-induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity-induced insulin resistance.

Keywords: insulin resistance; mitochondrial dynamics; obesity; skeletal muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / pharmacology*
  • Anti-Obesity Agents / therapeutic use
  • Cells, Cultured
  • Diet, High-Fat / adverse effects
  • Dynamins / antagonists & inhibitors*
  • Glucose / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / metabolism
  • Quinazolinones / pharmacology*
  • Quinazolinones / therapeutic use

Substances

  • 3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone
  • Anti-Obesity Agents
  • Insulin
  • Quinazolinones
  • Dnm1l protein, mouse
  • Dynamins
  • Glucose