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 SIRT1 has been proposed as a therapeutic strategy to treat mitochondrial dysfunction and insulin resistance in skeletal muscle. However, life-long overexpression of SIRT1 in skeletal muscle does not improve parameters of mitochondrial function and insulin sensitivity. In this study we investigated whether temporal overexpression of SIRT1 in muscle of adult mice would affect skeletal muscle mitochondrial function and insulin sensitivity. Methods To circumvent potential effects of germline SIRT1 overexpression, we utilized an inducible model of SIRT1 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 SIRT1 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 SIRT1 overexpression. Conclusion These results support previous work demonstrating that induction of SIRT1 in skeletal muscle, either at birth or in adulthood, does not impact muscle insulin action or mitochondrial function.

Fatty acid type–specific regulation of SIRT1 does not affect insulin sensitivity in human skeletal muscle

“…Correspondingly, muscle‐specific overexpression of SIRT1 was recently shown not to prevent glucose intolerance and impairment in insulin‐stimulated glucose uptake in mice after 12 wk of 60 E% HFD (36). Further, lean mice with either a conventional, germ line (37), or an acute inducible (38) skeletal muscle‐specific overexpression of SIRT1 did not enhance skeletal muscle insulin‐stimulated glucose uptake. Positive effects of SIRT1 activation on insulin‐stimulated glucose uptake with small molecule activators (2, 3) or via increasing NAD + availability (4–6) in insulin‐resistant rodents may likely be explained by effects of SIRT1 in other tissues than skeletal muscle.…”

Skeletal muscle in the fight against chronic diseases

“…While lifelong overexpression of SIRT1 in skeletal muscle did not improve insulin resistance, it was suggested that a temporal overexpression of SIRT1 in muscle of adult mice would affect insulin sensitivity of skeletal muscle. However, this hypothesis could not be confirmed …”

“…Another proposed strategy to treat insulin resistance in skeletal muscle and thereby diabetes is the activation of the NAD + ‐dependent protein deacetylase sirtuin 1 (SIRT1) . SIRT1 plays a role in changes in cellular energy status to adaptive changes in insulin signalling.…”

“…Another proposed strategy to treat insulin resistance in skeletal muscle and thereby diabetes is the activation of the NAD + -dependent protein deacetylase sirtuin 1 (SIRT1). 15 SIRT1 plays a role in changes in cellular energy status to adaptive changes in insulin signalling. The activity of SIRT1 is enhanced in skeletal muscle in calorie restriction and causes beneficial effects on glucose uptake stimulated by insulin.…”

“…However, this hypothesis could not be confirmed. 15 The risk of cardiovascular disease is increased in patients with chronic kidney disease, due to a disturbed cardiac metabolism, a reduced glucose utilization and increase in the uptake of free fatty acids. 16,17 A reduction in vessel relaxation, which is so far reported for vessel ageing, was analysed in terms of chronic renal failure.…”