Abstract
We have previously reported that the expression of mitochondrial deacetylase SIRT3 is high in the slow oxidative muscle and that the expression of muscle SIRT3 level is increased by dietary restriction or exercise training. To explore the function of SIRT3 in skeletal muscle, we report here the establishment of a transgenic mouse model with muscle-specific expression of the murine SIRT3 short isoform (SIRT3M3). Calorimetry study revealed that the transgenic mice had increased energy expenditure and lower respiratory exchange rate (RER), indicating a shift towards lipid oxidation for fuel usage, compared to control mice. The transgenic mice exhibited better exercise performance on treadmills, running 45% further than control animals. Moreover, the transgenic mice displayed higher proportion of slow oxidative muscle fibers, with increased muscle AMPK activation and PPARδ expression, both of which are known regulators promoting type I muscle fiber specification. Surprisingly, transgenic expression of SIRT3M3 reduced muscle mass up to 30%, likely through an up-regulation of FOXO1 transcription factor and its downstream atrophy gene MuRF-1. In summary, these results suggest that SIRT3 regulates the formation of oxidative muscle fiber, improves muscle metabolic function, and reduces muscle mass, changes that mimic the effects of caloric restriction.
Highlights
Caloric restriction (CR) prolongs animal lifespan and delays the onset of age-related diseases [1,2]
Generation of Muscle-specific SIRT3 Transgenic Mice SIRT3 expression is high in slow oxidative muscle and is increased by exercise training or caloric restriction [8]
In agreement with previous characterization of the muscle creatine kinase (MCK) promoter/enhancer element [57], the transgene mRNA was highly expressed in skeletal muscle, with a lower expression in heart and no expression in other tissues, such as adipose tissue (Fig. 1B)
Summary
Caloric restriction (CR) prolongs animal lifespan and delays the onset of age-related diseases [1,2]. CR increases insulin sensitivity, modulates protein turnover and protects against the aging-related decline of mitochondrial activity and muscle function [3,4,5]. SIRT3, a sirtuin family member of NAD+-dependent deacetylase, is the major mitochondrial protein deacetylase [6]. SIRT3 expression is increased in response to fasting or caloric restriction [7,8,9]. In the liver, SIRT3 deacetylates long-chain acyl CoA dehydrogenase (VCAD) to boost fatty acids b-oxidation [10], 3hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) to increase ketogenesis [11], acetyl-CoA synthetase 2 (ACS2) to utilize acetate [12,13], and ornithine transcarbamoylase (OTC) to detoxificate urea [9]. SIRT3deficient mice have greatly decreased levels of tissue adenosine triphosphate (ATP) [14], impaired cold tolerance when fasted [10], and more susceptibility to cardiac hypertrophy [21,22], breast cancer [23] and high-fat diet-induced metabolic syndrome [24,25]
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