Skeletal Muscle Fibre-Specific Knockout of p53 Does Not Reduce Mitochondrial Content or Enzyme Activity.

Ben Stocks,Andrew Philp,Carrie E Mccurdy,Sophie Joanisse,Jessica R Dent

doi:10.3389/fphys.2017.00941

Ben Stocks, Andrew Philp + Show 3 more

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https://doi.org/10.3389/fphys.2017.00941

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Abstract

Tumour protein 53 (p53) has been implicated in the regulation of mitochondrial biogenesis in skeletal muscle, with whole-body p53 knockout mice displaying impairments in basal mitochondrial content, respiratory capacity, and enzyme activity. This study aimed to determine the effect of skeletal muscle-specific loss of p53 on mitochondrial content and enzyme activity. Mitochondrial protein content, enzyme activity and mRNA profiles were assessed in skeletal muscle of 8-week-old male muscle fibre-specific p53 knockout mice (p53 mKO) and floxed littermate controls (WT) under basal conditions. p53 mKO and WT mice displayed similar content of electron transport chain proteins I-V and citrate synthase enzyme activity in skeletal muscle. In addition, the content of proteins regulating mitochondrial morphology (MFN2, mitofillin, OPA1, DRP1, FIS1), fatty acid metabolism (β-HAD, ACADM, ACADL, ACADVL), carbohydrate metabolism (HKII, PDH), energy sensing (AMPKα2, AMPKβ2), and gene transcription (NRF1, PGC-1α, and TFAM) were comparable in p53 mKO and WT mice (p > 0.05). Furthermore, p53 mKO mice exhibited normal mRNA profiles of targeted mitochondrial, metabolic and transcriptional proteins (p > 0.05). Thus, it appears that p53 expression in skeletal muscle fibres is not required to develop or maintain mitochondrial protein content or enzyme function in skeletal muscle under basal conditions.

Highlights

Tumour protein p53 (p53) was initially characterised as a tumour suppressor protein (Matoba et al, 2006; Vousden and Prives, 2009; Muller and Vousden, 2013), serving to regulate cellular metabolism and proliferation (Zhou et al, 2003; Bensaad et al, 2006; Matoba et al, 2006)
Non-myofibrillar p53 staining is apparent in both WT and Muscle fibre-specific knockout (mKO) muscle suggesting that the remaining p53 apparent in immunoblots of mKO muscle likely reflects expression from non-muscle fibre cells resident within skeletal muscle tissue
We report that muscle-specific deletion of p53 does not reduce mitochondrial protein content or enzyme activity within skeletal p53 and Skeletal Muscle Mitochondrial Biogenesis muscle

Summary

Introduction

Tumour protein p53 (p53) was initially characterised as a tumour suppressor protein (Matoba et al, 2006; Vousden and Prives, 2009; Muller and Vousden, 2013), serving to regulate cellular metabolism and proliferation (Zhou et al, 2003; Bensaad et al, 2006; Matoba et al, 2006). A functional role of p53 for in vivo skeletal muscle physiology has been proposed, following observations that p53 can regulate apoptosis (Saleem et al, 2009), atrophy (Fox et al, 2014), autophagy (Saleem et al, 2014), mitochondrial DNA stability (Saleem and Hood, 2013; Safdar et al, 2016), post-exercise signalling (Saleem et al, 2009, 2014), mitochondrial function (Park et al, 2009; Saleem et al, 2009, 2014; Wang et al, 2013) and endurance performance (Park et al, 2009; Saleem et al, 2009; Wang et al, 2013) within skeletal muscle. It is clear that p53 plays an important role in mitochondrial metabolism and function

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