Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1α/mitofusin-2 regulatory pathway in response to physical activity.

Abstract

Objective. Type 2 diabetes is associated with insulin resistance and skeletal muscle mitochondrial dysfunction. We have found that subjects with early-onset type 2 diabetes show an incapacity to increase VO₂max in response to chronic exercise. This suggests a defect in muscle mitochondrial response to exercise. Here, we have explored the nature of the mechanisms involved.

Methods. Muscle biopsies were collected from young type 2 diabetes subjects and obese controls before and after acute or chronic exercise protocols, and the expression of genes and/or proteins relevant to mitochondrial function was measured. In particular, the regulatory pathway PGC-1α/mitofusin-2 (Mfn2) was analyzed.

Results. At baseline, subjects with diabetes showed reduced expression (by 26%) of the mitochondrial fusion protein, Mfn2 and a 39% reduction of the α-subunit of ATP synthase. Porin expression was unchanged, consistent with normal mitochondrial mass. Chronic exercise led to a 2.8-fold increase in Mfn2, as well as increases in porin, and the α- subunit of ATP synthase in muscle from control subjects. However, Mfn2 was unchanged following chronic exercise in those with diabetes while porin and α-subunit of ATP synthase were increased. Acute exercise caused a 4-fold increase in PGC-1α expression in muscle from control subjects but not in those with diabetes.

Conclusions. Our results demonstrate alterations in the regulatory pathway that controls PGC-1α expression, and induction of Mfn2 in muscle from patients with early onset type 2 diabetes. Patients with early-onset type 2 diabetes display abnormalities in the exercise-dependent pathway that regulates the expression of PGC-1α and Mfn2.