Skeletal muscle
sirtuin 1 (
SIRT1) expression is reduced under
insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and
obesity. Herein, we investigated whether constitutive activation of
SIRT1 in skeletal muscle prevents HFD-induced muscle
insulin resistance. To address this, mice with muscle-specific overexpression of
SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body
glucose metabolism was assessed by oral
glucose tolerance test, and
insulin-stimulated
glucose uptake was measured at a physiological
insulin concentration in isolated soleus and extensor digitorum longus muscles. Although
SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice,
body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in
glucose tolerance and
insulin-mediated activation of
glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the
SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of
SIRT1 in skeletal muscle alone does not prevent HFD-induced
glucose intolerance,
weight gain, or
insulin resistance.