Mitochondrial dysfunction in skeletal muscle contributes to the development of acute insulin resistance in mice

Abstract

Background Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. Methods Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). Results Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P < 0.01), ATP production (−88.0%, P < 0.01), mtDNA (−53.1%, P < 0.01), and mitochondrial respiration (−52.2% for maximal respiration, P < 0.05) in skeletal muscle but not in liver. Administration of mdivi‐1 attenuated IR development by increasing mitochondrial function (+58.5% for mtDNA content, P < 0.01; 4.06 ± 0.69 to 5.84 ± 0.95 pmol/min/mg for citrate synthase activity, P < 0.05; 13.06 ± 0.70 to 34.87 ± 0.70 pmol/min/g for maximal respiration, P < 0.001). Western blot analysis showed acute IR resulted in increased autophagy (mitophagy) and UPRmt induction in muscle tissue. This adaptive response was inhibited by mdivi‐1, which reduced the mitochondrial oxidative stress of skeletal muscle during acute IR. Conclusions Acute IR induced mitochondrial oxidative stress that impaired mitochondrial function in skeletal muscle. Improving mitochondrial function has important potential for treating acute IR.

The specific mitochondrial unfolded protein response in fast- and slow-twitch muscles of high-fat diet-induced insulin-resistant rats

“…These results indicate that the HFD-induced UPRmt is mainly activated in slow-twitch muscle. Consistent with our results, a recent study demonstrated that the UPRmt could be activated in mouse skeletal muscle by short-term HFD feeding ( 27 ). Similarly, in mouse epididymal white adipose tissue (eWAT), the UPRmt was activated after unsaturated fish oil diet (UFD) feeding ( 42 ).…”

“…( 26 ) demonstrated that in long-term high-fat high-sucrose-fed animals, nicotinamide riboside could increase sirtuin-mediated UPRmt activation, triggering an adaptive process to increase hepatic β-oxidation and mitochondrial complex content and activity. A recent study demonstrated that UPRmt markers were elevated in acute insulin resistance in skeletal muscle induced by a high-fat diet ( 27 ). This research indicated that mitochondrial damage from a high-fat diet (HFD) induced the UPRmt as a stress response in skeletal muscle.…”

Deciphering the “obesity paradox” in the elderly: A systematic review and meta‐analysis of sarcopenic obesity

“…118 In mice, short-term high-fat diet induced muscular mitochondrial dysfunction and insulin resistance, which could be reversed upon recovery of muscle mitochondrial function. 119 These findings supported skeletal muscle as a new therapeutic target for diabetes. Patients with SO had muscle loss and excess fat accumulation, which increased the risks of metabolic diseases.…”

“…Skeletal muscle dysfunction is associated with impaired glucose homeostasis and insulin sensitivity 118 . In mice, short‐term high‐fat diet induced muscular mitochondrial dysfunction and insulin resistance, which could be reversed upon recovery of muscle mitochondrial function 119 . These findings supported skeletal muscle as a new therapeutic target for diabetes.…”

Mitochondrial Dynamics and Mitophagy in Cardiometabolic Disease

“…Interestingly, a study found that Mdivi-1 attenuates oxidative stress and exerts vascular protection in I/R injury through a mechanism unrelated to DRP1 activity, possibly due to elevated levels of antioxidant enzymes, SOD1, and catalase, as well as Nrf2 expression (176). Insulin resistance co-occurs with mitochondrial dysfunction in skeletal muscle, and Mdivi-1 can reduce insulin resistance by enhancing mitochondrial function (177,178).…”