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

OBJECTIVEType 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 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.RESEARCH DESIGN AND METHODSMuscle 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 γ coactivator (PGC)-1α/mitofusin-2 (Mfn2) was analyzed.RESULTSAt 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 after chronic exercise in individuals with diabetes, whereas porin and α-subunit of ATP synthase were increased. Acute exercise caused a fourfold increase in PGC-1α expression in muscle from control subjects but not in subjects with diabetes.CONCLUSIONSOur 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.

Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis

“…Here, we demonstrate that Mfn2 deficiency in mice induces susceptibility to develop insulin resistance in response to both age and HFD treatment. These data fit with the observations that muscle Mfn2 is repressed in human obesity or in type 2 diabetes (13,14) and allow us to propose that Mfn2 is a regulator of in vivo insulin sensitivity and a potential target in diabetes drug development.…”

“…Mfn2 is relevant in human disease, and mutations in Mfn2 have been reported in patients affected by Charcot-Marie-Tooth neuropathy type 2A (10)(11)(12). In addition, we have reported that Mfn2 expression is reduced in skeletal muscle of obese subjects and in type 2 diabetic patients (13,14).…”

Impaired overload-induced hypertrophy is associated with diminished mTOR signaling in insulin-resistant skeletal muscle of the obese Zucker rat

“…Previous data from our laboratory have suggested that the capacity of the OZ soleus muscle to undergo hypertrophy in response to increased loading is diminished compared with that observed in the lean Zucker (LZ) rat. Why metabolic syndrome may affect the hypertrophic response of muscle is not clear although we and others have noted that insulin resistance is associated with differences in the ability of skeletal muscle to activate intracellular signaling cascades in response to alterations in contractile activity (14,19,20,34).…”

Mitofusin-2 prevents skeletal muscle wasting in cancer cachexia

“…Inhibition of mitochondrial fission has been shown to inhibit muscle loss during fasting (11,15). In addition, downregulation of Mfn2 has been observed in the muscle of obese and non-obese type 2 diabetic subjects (16,17), and decreased mRNA expression levels of Mfn2 were observed in the skeletal muscle of tumor-bearing mice with severe cachexia (11). These results suggested that Mfn2 is involved in muscle wasting associated with diseases such as cancer cachexia.…”