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Submitted on January 3, 2006
Accepted on May 3, 2006
Division of Endocrinology and Metabolism, Department of Medicine, and the Structural Biology Imaging Center, Department of Cell Biology at the University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213
* To whom correspondence should be addressed. E-mail: toledofs{at}upmc.edu.
Context: In obesity, skeletal muscle insulin resistance may be associated with smaller mitochondria. Objective: To examine the effect of a lifestyle modification intervention on the content and morphology of skeletal muscle mitochondria, and its relationship to insulin sensitivity in obese, insulin-resistant subjects. Design: Prospective interventional study. Inter-myofibrillar mitochondrial content and size were quantified by transmission electron microscopy with quantitative morphometric analysis of biopsy samples from vastus lateralis muscle. Systemic insulin sensitivity was measured with euglycemic hyperinsulinemic clamps. Setting: University-based clinical research center. Participants: 11 sedentary, overweight/obese volunteers without diabetes. Intervention: 16 weeks of aerobic training with dietary restriction of 500-1000 Kcal/day. Main outcome measures: changes in mitochondrial content, size and changes in insulin sensitivity. Results: the % of myofiber volume occupied by mitochondria significantly increased from 3.70 ± 0.31% to 4.87 ± 0.33% after intervention (P = 0.01). The mean individual increase was 42.5 ± 18.1%. There was also a change in the mean cross-sectional mitochondrial area, increasing from a baseline of 0.078 ± 0.007 µ2 to 0.091 ± 0.007 µ2 (P < 0.01); a mean increase of 19.2 ± 6.1% per subject. These changes in mitochondrial size and content highly correlated with improvements in insulin resistance (r=0.68 and 0.72, respectively, P = 0.01). Conclusions: a combined intervention of weight loss and physical activity in previously sedentary obese adults is associated with enlargement of mitochondria and an increase in the mitochondrial content in skeletal muscle. These findings indicate that in obesity with insulin resistance, ultrastructural mitochondrial plasticity is substantially retained and, importantly, that changes in the morphology of mitochondria are associated with improvements in insulin resistance.
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