Skeletal muscle and insulin resistance – a focus on mitochondria

G.D. Wadley, Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC 3125, Australia.

Skeletal muscle accounts for approximately 80% of insulin-stimulated glucose uptake and a key defect in the aetiology of type 2 diabetes (T2D) is the development of skeletal muscle insulin resistance (DeFronzo et al., 1985). It has been well documented that skeletal muscle of people with T2D have impaired mitochondrial function, with this being due to reduced mitochondrial content (Boushel et al., 2007). Furthermore, many of the regulatory components involved in mitochondrial biogenesis, such as peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) are also known to be reduced in the skeletal muscle of people with T2D (Patti et al., 2003). This led to the popular hypothesis that the reduction in mitochondrial content in T2D was causative in the development of skeletal insulin resistance, via the reduced capacity for lipid oxidation and subsequent accumulation of lipids that may impair insulin-stimulated glucose uptake (Patti et al., 2003). However, many studies who find reduced mitochondrial content in T2D are likely confounded by several factors, such as not controlling for reduced physical activity, which strongly impacts mitochondrial content (van Tienen et al., 2012). Therefore it appears that mitochondrial dysfunction, at least in humans with T2D, is secondary to the development of skeletal muscle insulin resistance.

Although mitochondrial dysfunction may not be causative in the development of skeletal muscle insulin resistance for T2D, it is still quite likely that improving skeletal muscle mitochondrial content and function could be causative in improving insulin resistance. Indeed, people with T2D respond to endurance training with normal increases in insulin sensitivity and skeletal muscle mitochondrial proteins (van Tienen et al., 2012). Furthermore, rodent studies that increase skeletal muscle mitochondria via electrotransfection of PGC-1α also improve skeletal muscle insulin sensitivity (Benton et al., 2010).

Mitochondria are responsible for the majority of skeletal muscle ROS production under basal (non contraction) conditions (Vasilaki et al., 2006) and there is now strong evidence linking mitochondrial ROS and skeletal muscle insulin resistance (Anderson et al., 2009; Hoehn et al., 2009). However, there is currently limited in vivo evidence to confirm if mitochondrial ROS levels are elevated in the skeletal muscle of people with T2D. Furthermore, despite the promising evidence of mitochondrial specific antioxidants reducing skeletal muscle insulin resistance in rodents (Anderson et al., 2009; Hoehn et al., 2009), evidence to support antioxidant therapies for the treatment of skeletal muscle insulin resistance in humans is lacking.

The mechanism for reduced ROS levels following increased mitochondrial content (e.g. after exercise training) is thought to be due to the elevated mitochondrial content per unit of tissue (i.e. more efficient respiration) (Mitsuishi et al., 2008). Importantly, high glucose levels in skeletal muscle cells, which is known to induce insulin resistance, increase mitochondrial ROS levels and this can be reversed in vitro, by increasing mitochondrial biogenesis and mitochondrial mass (Mitsuishi et al., 2008). Therefore, it is possible that a similar process may occur in skeletal muscle of people with T2D in response to exercise training. However, studies are now required to test if this also occurs in human or animal skeletal muscle.

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