Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1{alpha}/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 incapacity to increase Vo(2max) 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. RESEARCH DESIGN AND METHODS Muscle biopsies were collected from young type 2 diabetic subjects and obese control subjects 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 peroxisome proliferator-activated receptor gamma coactivator (PGC)-1alpha/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 alpha-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 alpha-subunit of ATP synthase in muscle from control subjects. However, Mfn2 was unchanged after chronic exercise in individuals with diabetes, whereas porin and alpha-subunit of ATP synthase were increased. Acute exercise caused a fourfold increase in PGC-1alpha expression in muscle from control subjects but not in subjects with diabetes. CONCLUSIONS Our results demonstrate alterations in the regulatory pathway that controls PGC-1alpha 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-1alpha and Mfn2.

Figure 1

A: Baseline: Young type 2 diabetic subjects show an impaired expression of mitochondrial proteins in skeletal muscle. Western blot assays were performed in extracts obtained from skeletal muscle biopsies from 11 normal glucose tolerant (control) and 16 young type 2 diabetic patients (young T2D). Data are means ± SE. *Statistically significant difference compared with the control group at P < 0.05. Representative autoradiograms are also shown. B: Chronic exercise. Chronic exercise causes a deficient induction of muscle mitochondrial proteins in young type 2 diabetic subjects. Western blot assays were performed in extracts obtained from skeletal muscle biopsies from normal glucose tolerant and young type 2 diabetic patients before and after a protocol of chronic exercise. Representative autoradiograms are shown in the lower right corner. Data are means ± SE. *Statistical significant difference compared with basal values at P < 0.05. C: Acute exercise. Acute exercise induces skeletal muscle PGC-1α gene expression in control but not in young type 2 diabetic subjects. Real-time PCR was performed in skeletal muscle biopsies from nine normal glucose tolerant and six young type 2 diabetic patients before and after an acute session of exercise. Data are means ± SE. *Statistical significant difference compared with basal values at P < 0.05.