A PGC-1 alpha- and muscle fibre type-related decrease in markers of mitochondrial oxidative metabolism in skeletal muscle of humans with inherited insulin resistance

作者：Kristensen Jonas M; Skov Vibe; Petersson Stine J; Ortenblad Niels; Wojtaszewski Jorgen F P; Beck Nielsen Henning; Hojlund Kurt^*

来源：Diabetologia, 2014, 57(5): 1006-1015.

DOI：10.1007/s00125-014-3187-y

• Gene expression
• Insulin resistance
• Mitochondria
• Muscle fibre type
• PGC-1 alpha
• Skeletal muscle

Aims/hypothesis Insulin resistance in obesity and type 2 diabetes is related to abnormalities in mitochondrial oxidative phosphorylation (OxPhos) in skeletal muscle. We tested the hypothesis that mitochondrial oxidative metabolism is impaired in muscle of patients with inherited insulin resistance and defective insulin signalling. %26lt;br%26gt;Methods Skeletal muscle biopsies obtained from carriers (n = 6) of a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR) and matched healthy controls (n = 15) were used for discovery-mode microarray-based transcriptional profiling combined with biological pathway analysis. Findings were validated by quantitative real-time PCR, immunoblotting and activity assays. %26lt;br%26gt;Results In INSR mutation carriers, insulin resistance was associated with a coordinated downregulation of OxPhos genes in skeletal muscle. This was related to a 46% decrease in mRNA levels (p = 0.036) of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), and 25-50% lower protein content of OxPhos subunits encoded by mitochondrial (ND6, p = 0.042) and nuclear DNA (UQCRC1, p = 0.001; SDHA, p = 0.067; COX5A, p = 0.017 and ATP5B, p = 0.005), as well as reduced citrate synthase activity (p = 0.025). Moreover, mutation carriers showed a marked reduction in type 1 muscle fibres (35% vs 62%, p = 0.0005) and increased type 2a fibres (53% vs 32%; p = 0.002) compared with controls. There were no differences in protein content and phosphorylation of 5%26apos; AMP-activated protein kinase, p38 mitogen-activated protein kinase, Erk1 and Erk2. %26lt;br%26gt;Conclusions/interpretation These data indicate that inherited insulin resistance coincides with reduced mitochondrial oxidative capacity in a PGC-1 alpha- and muscle fibre type-related manner. Whether this co-existence is directly or indirectly related to insulin resistance remains to be elucidated.

• 出版日期2014-5