The Role of Mitochondria in the Pathophysiology of Skeletal Muscle Insulin Resistance

Abstract

Multiple organs contribute to the development of peripheral insulin resistance, with the major contributors being skeletal muscle, liver, and adipose tissue. Because insulin resistance usually precedes the development of type 2 diabetes mellitus (T2DM) by many years, understanding the pathophysiology of insulin resistance should enable development of therapeutic strategies to prevent disease progression. Some subjects with mitochondrial genomic variants/defects and a subset of lean individuals with hereditary predisposition to T2DM exhibit skeletal muscle mitochondrial dysfunction early in the course of insulin resistance. In contrast, in the majority of subjects with T2DM the plurality of evidence implicates skeletal muscle mitochondrial dysfunction as a consequence of perturbations associated with T2DM, and these mitochondrial deficits then contribute to subsequent disease progression. We review the affirmative and contrarian data regarding skeletal muscle mitochondrial biology in the pathogenesis of insulin resistance and explore potential therapeutic options to intrinsically modulate mitochondria as a strategy to combat insulin resistance. Furthermore, an overview of restricted molecular manipulations of skeletal muscle metabolic and mitochondrial biology offers insight into the mitochondrial role in metabolic substrate partitioning and in promoting innate adaptive and maladaptive responses that collectively regulate peripheral insulin sensitivity. We conclude that skeletal muscle mitochondrial dysfunction is not generally a major initiator of the pathophysiology of insulin resistance, although its dysfunction is integral to this pathophysiology and it remains an intriguing target to reverse/delay the progressive perturbations synonymous with T2DM.

Neonatal overnutrition in mice exacerbates high-fat diet-induced metabolic perturbations

“…The impaired SKM insulin signaling is crucial for systemic insulin resistance and precedes the development of diabetes (DeFronzo & Tripathy 2009, Pagel-Langenickel et al 2010. However, our study showed that HFD exerts minor effects on Irs1 and Glut4 mRNA in SKM compared with the change in WAT, agreeing with a previous report (Anai et al 1999).…”

Mitochondrial biogenesis is decreased in skeletal muscle of pig fetuses exposed to maternal high-energy diets

“…Mitochondrial dysfunction was an important event in the development of T2D and insulin resistance in adult life (Pagel-Langenickel et al, 2010). It has been shown that maternal high-fat diet-induced changes in mitochondrial biogenesis in offspring are associated with decreased mitochondrial functions (Mohamed et al, 2014).…”

“…Skeletal muscle composes the largest metabolic tissue in the body and is one of the key insulinresponsive organs (Lowell and Shulman, 2005). Mitochondrial dysfunction in skeletal muscle has been associated with metabolic diseases in human and animal models (Pagel-Langenickel et al, 2010). Likewise, decreased oxidative phosphorylation, antioxidative capacity and mitochondrial electron transport chain enzyme activities in the liver and skeletal muscle have been observed in the offspring subjected to maternal overnutrition and diabetes (Bruce et al, 2009;Zhang et al, 2011;Latouche et al, 2014).…”

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

“…Additionally, recent work has also shown that, in the context of redox or direct proteotoxic stressors, SIRT3 in its capacity to enhance excess reactive oxygen species biology has an inverse, albeit indirect, and ameliorative effect on the mitochondrial protein folding machinery (43). Our study nevertheless advances the understanding of a mechanism that may explain the paradoxical findings, where nutrient excess and caloric restriction have profound effects on mitochondrial homeostasis and quality control (44,45). Further investigations into the mechanisms underpinning acetylation on the mitochondrial folding and unfolded protein responses should advance our insight into why caloric load can have direct effects on mitochondrial biology (44).…”

“…Our study nevertheless advances the understanding of a mechanism that may explain the paradoxical findings, where nutrient excess and caloric restriction have profound effects on mitochondrial homeostasis and quality control (44,45). Further investigations into the mechanisms underpinning acetylation on the mitochondrial folding and unfolded protein responses should advance our insight into why caloric load can have direct effects on mitochondrial biology (44).…”