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

  1. John J. Nolan, MD4
  1. 1Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain;
  2. 2Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain;
  3. 3CIBER de Diabetes y de Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain;
  4. 4Metabolic Research Unit, Department of Endocrinology, Hospital 5, St. James' Hospital, Trinity College Dublin, Dublin, Ireland;
  5. 5Institute of Internal Medicine, Catholic University School of Medicine, Rome, Italy.
  1. Corresponding author: John J. Nolan, jnolan{at}
  1. M.I.H.-A. and H.T. contributed equally to this work. A.Z. and J.J.N. share senior authorship.


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 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 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 γ coactivator (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 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.

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.


  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received July 22, 2009.
    • Accepted December 14, 2009.
| Table of Contents