Department of Orthopaedic Surgery, University of California San Diego, La Jolla, CA, USA.
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
Acta Physiol (Oxf). 2017 Nov;221(3):193-203. doi: 10.1111/apha.12897. Epub 2017 Jun 13.
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, lifelong 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.
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.
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.
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.
激活 NAD 依赖的蛋白去乙酰化酶 SIRT1 被提议作为一种治疗策略，以治疗骨骼肌中的线粒体功能障碍和胰岛素抵抗。然而，骨骼肌中 SIRT1 的终身过表达并不能改善线粒体功能和胰岛素敏感性的参数。在这项研究中，我们研究了成年小鼠肌肉中 SIRT1 的瞬时过表达是否会影响骨骼肌线粒体功能和胰岛素敏感性。
为了避免生殖系 SIRT1 过表达的潜在影响，我们利用成年小鼠骨骼肌中 SIRT1 过表达的诱导模型（i-mOX）。通过 2-脱氧葡萄糖摄取评估胰岛素敏感性，通过高分辨率呼吸测定法评估肌肉最大呼吸功能，通过全身热量测定法评估全身能量消耗。
尽管 i-mOX 小鼠的骨骼肌中 SIRT1 高度且特异性过表达，但与 WT 小鼠相比，葡萄糖耐量和骨骼肌胰岛素敏感性无差异。此外，线粒体生物发生的标志物、肌肉最大呼吸功能和全身耗氧量也不受 SIRT1 过表达的影响。
这些结果支持之前的工作，表明诱导 SIRT1 在骨骼肌中的表达，无论是在出生时还是在成年期，都不会影响肌肉胰岛素作用或线粒体功能。
