Context: In obesity, skeletal muscle insulin resistance may be associated with smaller mitochondria.

Objective: Our objective was 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: In this prospective interventional study, intermyofibrillar 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: The study took place at a university-based clinical research center.

Participants: Eleven sedentary, overweight/obese volunteers without diabetes participated in the study.

Intervention: Intervention included 16 wk of aerobic training with dietary restriction of 500-1000 kcal/d.

Main outcome measures: We assessed changes in mitochondrial content and size and changes in insulin sensitivity.

Results: The percentage 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 to 0.091 +/- 0.007 microm(2) (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.