title: 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.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Hernández-Alvarez
authors.forename: Hood
authors.initials: H
authors.lastname: Thabit
authors.forename: Nicole
authors.initials: N
authors.lastname: Burns
authors.forename: Syed
authors.initials: S
authors.lastname: Shah
authors.forename: Imad
authors.initials: I
authors.lastname: Brema
authors.forename: Mensud
authors.initials: M
authors.lastname: Hatunic
authors.forename: Francis
authors.initials: F
authors.lastname: Finucane
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.forename: Chiara
authors.initials: C
authors.lastname: Chiellini
authors.forename: Deborah
authors.initials: D
authors.lastname: Naon
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: John J
authors.initials: JJ
authors.lastname: Nolan
mesh_terms: D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation / Q000502:physiology; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human