Insulin-resistant muscle is exercise resistant: Evidence for reduced response of nuclear-encoded mitochondrial genes to exercise

Elena De Filippis, Guy Alvarez, Rachele Berria, Kenneth Cusi, Sarah Everman, Christian Meyer, Lawrence J. Mandarino

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121 Scopus citations


Mitochondrial dysfunction, associated with insulin resistance, is characterized by low expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and nuclear-encoded mitochondrial genes. This deficit could be due to decreased physical activity or a decreased response of gene expression to exercise. The objective of this study was to investigate whether a bout of exercise induces the same increase in nuclear-encoded mitochondrial gene expression in insulin-sensitive and insulin-resistant subjects matched for exercise capacity. Seven lean and nine obese subjects took part. Insulin sensitivity was assessed by an 80 mU·m-2·min-1 euglycemic clamp. Subjects were matched for aerobic capacity and underwent a single bout of exercise at 70 and 90% of maximum heart rate with muscle biopsies at 30 and 300 min postexercise. Quantitative RT-PCR and immunoblot analyses were used to determine the effect of exercise on gene expression and protein abundance and phosphorylation. In the postexercise period, lean subjects immediately increased PGC-1α mRNA level (reaching an eightfold increase by 300 min postexercise) and protein abundance and AMP-dependent protein kinase phosphorylation. Activation of PGC-1α was followed by increase of nuclear respiratory factor-1 and cytochrome c oxidase (subunit VIc). However, in insulin-resistant subjects, there was a delayed and reduced response in PGC-1α mRNA and protein, and phosphorylation of AMP-dependent protein kinase was transient. None of the genes downstream of PGC-1α was increased after exercise in insulin resistance. Insulin-resistant subjects have a reduced response of nuclear-encoded mitochondrial genes to exercise, and this could contribute to the origin and maintenance of mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)E607-E614
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number3
StatePublished - Mar 2008


  • AMP-dependent protein kinase
  • Exercise
  • Insulin resistance
  • Mitochondrial function
  • Peroxisome proliferator-activated receptor-γ coactivator-1α

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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