SKELETAL MUSCLE MITOCHONDRIAL CAPACITY PLAYS A MINIMAL ROLE IN MEDIATING INSULIN SIGNALING AND REGULATION IN INDIVIDUALS WITH IMPAIRED GLYCEMIC CONTROL

Abstract

<p>This thesis examined the biochemical role of skeletal muscle mitochondria and metabolic consequences of mitochondrial adaptations to exercise in individuals with poor glycemic control. Mitochondrial dysfunction and/or ectopic lipid accumulation has been implicated in the pathogenesis of metabolic-related diseases such as obesity and type 2 diabetes (T2D). However, whether mitochondrial dysfunction is the cause of insulin resistance and T2D or is a consequence of this disorder remains controversial. Alternatively, pro-inflammatory stress signals initiated through altered secretion of adipocytokines and oxidative stress may be a unifying mechanism underlying insulin resistance and T2D. Furthermore, the impact of exercise on muscle adaptation in insulin-resistant states is not well defined. At rest and prior to exercise training, no evidence of mitochondrial dysfunction or disproportionate intramyocellular lipid (IMCL) accretion was detected in obese, insulin-resistant skeletal muscle biopsy samples <em>vs.</em> healthy, lean age-, and fitness-matched men. In response to exercise training (12 weeks, consisting of 32 sessions of 30-60 min @ 50-70% maximal oxygen uptake [VO₂peak]), there was an increase in mitochondrial oxidative phosphorylation (OXPHOS) capacity, mitochondrial content, and IMCL deposition with sub-cellular specificity. Exercise training also reduced both skeletal muscle and systemic oxidative damage, already elevated in the obese. The improved adipocytokine profile associated with obesity after training also coincided with improvements in glycemic regulation. Patients with genetic mitochondrial mutations, resulting in skeletal muscle mitochondrial dysfunction have an increase prevalence of dysglycemia/T2D. However, when evaluated against age- and activity-matched normoglycemic myopathy controls, no differences in mitochondrial electron transport chain protein subunits, mitochondrial or IMCL density, or level of whole-body insulin resistance was detected. In fact, dysglycemic mitochondrial myopathy patients demonstrated <em>higher </em>skeletal muscle OXPHOS capacity and Akt activation, a key step in insulin-stimulated glucose transport activity as compared with normoglycemic mitochondrial myopathy patients. Interestingly, a significant impairment in β-cell function (defective insulin secretion), in the dysglycemic patients was observed coincident with elevated glucose levels during the oral glucose tolerance test (OGTT). These findings indicate that insulin resistance does not cause skeletal muscle mitochondrial dysfunction/IMCL accumulation or <em>vice versa</em> and provides evidence against a direct link between mitochondrial dysfunction and the development of insulin resistance/T2D. Perhaps, oxidative stress/inflammation and pancreatic β-cell erosion mediate the observed obesity-induced insulin resistance and mitochondrial myopathy-associated T2D, respectively? Twelve weeks of moderate endurance exercise is an effective strategy to improve mitochondrial capacity, oxidative damage, inflammation, and glycemic regulation in insulin-resistant, obese individuals, but an improvement in muscle insulin sensitivity did not appear to be required.</p>