Mitochondrial Involvement in Skeletal Muscle Insulin Resistance
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
- Corresponding author: Frederico G.S. Toledo, .
Conflict and mystery are key elements of great suspense stories. Over the last decade, those elements have been present in an intriguing story that has attracted a lot of attention in the field of insulin resistance (IR). The story takes place in a complex scenario: a mix of genetic and acquired abnormalities. The story’s victim is insulin sensitivity in skeletal muscle, but the perpetrators remain fittingly elusive. Suspicions fall on intramyocellular lipid oversupply being the villain. According to prevailing theory, skeletal muscle IR develops as a consequence of excessive lipid content within this tissue. However, it has become increasingly evident that lipid oversupply does not act alone in this story. During the last decade, mitochondria have emerged as an “organelle of interest,” with alleged roles ranging from accomplice to collateral-damage casualty.
A role for mitochondria in IR emerged when studies reported lower mitochondrial oxidative capacity in skeletal muscle of adults with obesity and/or type 2 diabetes (1,2). Other studies concurrently reported lower mitochondrial activity in IR linked to aging and possibly to genetic background in lean individuals with parental history of type 2 diabetes (3–5). Those reports attracted a lot of interest and gave rise to an appealing idea that mitochondrial deficiency may be an important factor in the pathogenesis of IR. According to such a view, a decrease in total mitochondrial oxidative capacity, due to loss in mitochondrial content and/or function, results in insufficient lipid oxidation with the postulated effect being exacerbation of lipid excess and consequent IR.
A surge of research studies and opinions followed, adding conflict and challenging twists to the story. In specific experimental conditions, the lower mitochondrial capacity seen in IR appears to be secondary to impaired stimulatory action of insulin on mitochondrial biogenesis (6). However, other studies have shown that in physiological conditions, lower mitochondrial capacity is not explained by chronic reductions in insulin action (7,8). The mitochondrial deficits associated with obesity and even type 2 diabetes were found to respond well to moderate exercise, suggesting an acquired contribution of sedentary lifestyle (7,9,10). Further, a role for mitochondria was reasonably questioned because skeletal muscle is endowed with considerable functional reserve; thus, in theory, a modest deficiency would not be anticipated to reduce lipid oxidation (11). Despite these considerations, a mitochondrial DNA defect linked to impaired mitochondrial oxidation was linked to IR in vivo in humans (12) and lower muscle mitochondrial content correlates with decreased reliance on lipid oxidation during fasting (13), suggesting that it may be premature to dismiss a relationship between mitochondria and fuel homeostasis in humans.
Animal studies added their measure of controversy too. In rats, high-fat feeding was associated with higher mitochondrial capacity (14), thereby revealing interspecies differences between rodent and human physiology that creates challenges for advancing the field. Animal studies have also uncovered the possibility that IR may be related to incomplete intramitochondrial beta-oxidation (15). Together, human and animal studies have revealed that models of IR are incomplete without an understanding of how mitochondria are involved. The enigma persists, nonetheless, as to what causes mitochondria to be seemingly abnormal in the first place and whether the abnormalities contribute partially, or not at all, to the development of IR.
In this issue, Fisher-Wellman et al. (16) add a new chapter to this intriguing story. The authors reasoned that if a deficit in mitochondrial capacity is central to the pathogenesis of IR, then it would be expected to predate its onset. To this end, they studied young (∼23 years old) nondiabetic adults, both lean and obese. Mitochondrial oxidative capacity was studied in permeabilized myofibers and primary myotubes from muscle biopsies. Not surprisingly, the obese group was insulin-resistant. However, various measures of mitochondrial oxidative capacity were not diminished despite obvious IR. In search of alternate explanations, the authors found that mitochondrial H2O2 emission was increased, bolstering a previous report from the same group implicating oxidative stress in the pathogenesis of IR (17).
The results of Fisher-Wellman et al. (16) are important because they demonstrate that lower oxidative capacity is not a requirement for the early phases of development of IR—at least the type of IR observed in obesity. However, the study’s findings still leave open the possibility that when mitochondrial capacity is diminished it might synergistically contribute to reducing insulin sensitivity. This remains plausible because a group of obese individuals with lower mitochondrial oxidative capacity was not included in the study. It remains unknown whether such individuals would have even worse IR. Furthermore, it is worth noting that it is unlikely that IR is best explained by a single cause. Rather, it is more likely that IR may develop as a result of multiple yet complementary mechanisms. For instance, IR of obesity may develop due to reasons other than those seen in the lean offspring of individuals with type 2 diabetes, in whom mitochondrial deficits precede obesity (4,5). Therefore, a putative pathogenic role for mitochondria remains unsettled.
In obesity, unequivocally lower mitochondrial content in skeletal muscle has been clearly documented by electron microscopy (13). It has also been documented by enzymatic biomarkers such as citrate synthase activity (18–20). An expected consequence is lower muscle respiratory capacity, which has also been reported (20). Thus, the findings of Fisher-Wellman et al. (16) seemingly contradict previous literature. However, a distinguishing feature of the new report was the inclusion of relatively younger subjects, hinting that the mitochondrial abnormalities in IR obesity might be age-dependent. If true, the reasons are not immediately clear. One possibility is that certain young obese individuals have enough compensatory reserve for mitochondrial biogenesis and thus deficiencies would be hard to observe. Aging is associated with decreased mitochondrial biogenesis, which might explain why older individuals in previous studies exhibited more obvious relationships between mitochondria and IR (Fig. 1). We have yet to uncover exactly how mitochondria interact with nutrient excess, and whether they confer pathophysiological consequences to glucose and lipid homeostasis as well as oxidative stress. Clearly, more research is needed to finish the remaining chapters of this suspense story.
Acknowledgments. The author would like to thank James DeLany, PhD (University of Pittsburgh) for helpful discussion in the preparation of the manuscript.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
- © 2014 by the American Diabetes Association.
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