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

    Research output: Contribution to journalArticle

    102 Citations (Scopus)

    Abstract

    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)
    JournalAmerican Journal of Physiology - Endocrinology and Metabolism
    Volume294
    Issue number3
    DOIs
    StatePublished - Mar 2008

    Fingerprint

    Mitochondrial Genes
    Muscle
    Genes
    Insulin
    Insulin Resistance
    Muscles
    Phosphorylation
    Adenosine Monophosphate
    Gene Expression
    Protein Kinases
    Gene expression
    Nuclear Respiratory Factor 1
    Messenger RNA
    Peroxisome Proliferator-Activated Receptors
    Proteins
    Glucose Clamp Technique
    Electron Transport Complex IV
    Heart Rate
    Maintenance
    Biopsy

    Keywords

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

    ASJC Scopus subject areas

    • Physiology
    • Endocrinology
    • Biochemistry

    Cite this

    Insulin-resistant muscle is exercise resistant : Evidence for reduced response of nuclear-encoded mitochondrial genes to exercise. / De Filippis, Elena; Alvarez, Guy; Berria, Rachele; Cusi, Kenneth; Everman, Sarah; Meyer, Christian; Mandarino, Lawrence J.

    In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 294, No. 3, 03.2008.

    Research output: Contribution to journalArticle

    De Filippis, Elena ; Alvarez, Guy ; Berria, Rachele ; Cusi, Kenneth ; Everman, Sarah ; Meyer, Christian ; Mandarino, Lawrence J. / Insulin-resistant muscle is exercise resistant : Evidence for reduced response of nuclear-encoded mitochondrial genes to exercise. In: American Journal of Physiology - Endocrinology and Metabolism. 2008 ; Vol. 294, No. 3.
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