Insulin-resistant muscle is exercise resistant: evidence for reduced response of nuclear-encoded mitochondrial genes to exercise.
Mitochondrial dysfunction, associated with insulin resistance, is characterized by low expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) 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-1alpha mRNA level (reaching an eightfold increase by 300 min postexercise) and protein abundance and AMP-dependent protein kinase phosphorylation. Activation of PGC-1alpha 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-1alpha mRNA and protein, and phosphorylation of AMP-dependent protein kinase was transient. None of the genes downstream of PGC-1alpha 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.
De Filippis
Elena
E
Center for Metabolic Biology, Arizona State University, P. O. Box 873704 Tempe, AZ 85287-3704, USA.
Alvarez
Guy
G
Berria
Rachele
R
Cusi
Kenneth
K
Everman
Sarah
S
Meyer
Christian
C
Mandarino
Lawrence J
LJ
D000328:Adult; D002467:Cell Nucleus / Q000737:chemistry; D015444:Exercise; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D050259:Genes, Mitochondrial / Q000235:genetics*; D015309:Glucose Clamp Technique; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000502:physiology; D009124:Muscle Proteins / Q000032:analysis; D018482:Muscle, Skeletal / Q000503:physiopathology* / Q000648:ultrastructure; D009765:Obesity / Q000503:physiopathology; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics
D006360:Heat-Shock Proteins; D009124:Muscle Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D012333:RNA, Messenger; D014157:Transcription Factors