Temporal overexpression of SIRT1 in skeletal muscle of adult mice does not improve insulin sensitivity or markers of mitochondrial biogenesis

Abstract Aims Activation of the NAD + dependent protein deacetylase SIRT 1 has been proposed as a therapeutic strategy to treat mitochondrial dysfunction and insulin resistance in skeletal muscle. However, lifelong overexpression of SIRT 1 in skeletal muscle does not improve parameters of mitochondrial function and insulin sensitivity. In this study, we investigated whether temporal overexpression of SIRT 1 in muscle of adult mice would affect skeletal muscle mitochondrial function and insulin sensitivity. Methods To circumvent potential effects of germline SIRT 1 overexpression, we utilized an inducible model of SIRT 1 overexpression in skeletal muscle of adult mice (i‐ mOX ). Insulin sensitivity was assessed by 2‐deoxyglucose uptake, muscle maximal respiratory function by high‐resolution respirometry and systemic energy expenditure was assessed by whole body calorimetry. Results Although SIRT 1 was highly, and specifically, overexpressed in skeletal muscle of i‐ mOX compared to WT mice, glucose tolerance and skeletal muscle insulin sensitivity were comparable between genotypes. Additionally, markers of mitochondrial biogenesis, muscle maximal respiratory function and whole‐body oxygen consumption were also unaffected by SIRT 1 overexpression. Conclusion These results support previous work demonstrating that induction of SIRT 1 in skeletal muscle, either at birth or in adulthood, does not impact muscle insulin action or mitochondrial function.