p53 Improves Aerobic Exercise Capacity and Augments Skeletal Muscle Mitochondrial DNA Content

Abstract

Rationale: Exercise capacity is a physiological characteristic associated with protection from both cardiovascular and all-cause mortality. p53 regulates mitochondrial function and its deletion markedly diminishes exercise capacity, but the underlying genetic mechanism orchestrating this is unclear. Understanding the biology of how p53 improves exercise capacity may provide useful insights for improving both cardiovascular as well as general health. Objective: The purpose of this study was to understand the genetic mechanism by which p53 regulates aerobic exercise capacity. Methods and Results: Using a variety of physiological, metabolic, and molecular techniques, we further characterized maximum exercise capacity and the effects of training, measured various nonmitochondrial and mitochondrial determinants of exercise capacity, and examined putative regulators of mitochondrial biogenesis.As p53 Key Words: aerobic Ⅲ exercise Ⅲ mitochondrial DNA Ⅲ p53 Ⅲ TFAM A cross populations aerobic exercise capacity inversely correlates with cardiovascular disease and all-cause mortality. 1-3 Our report of a marked reduction in the maximal exercise capacity of p53 homozygous knockout (p53 Ϫ/Ϫ ) mice and subsequent confirmation by others provided physiological evidence for p53 as an important mediator of aerobic metabolism. 4,5 We previously showed that p53 promotes mitochondrial respiration in human and murine cells by regulating the transcription of Synthesis of Cytochrome c Oxidase 2 (SCO2), a gene essential for oxidative phosphorylation. 4,6 A concurrent report demonstrating that p53 directly suppresses glycolysis through TIGAR, a p53-dependent regulator of glycolysis and apoptosis, suggested that p53 can coordinate aerobic and glycolytic metabolism. 7 Multiple factors contribute to aerobic exercise capacity, but one major determinant is the mitochondrial content of skeletal muscle as demonstrated by a genetic selection experiment. 8 A recent study showed decreased mitochondrial density in the skeletal muscle of p53-deficient mice, 5 but the genetic mechanism orchestrating this change has remained unclear. A number of other studies have also associated p53 with exercise response and mitochondrial function. For example, p53 levels are increased after acute exercise, and the transition from glycolysis to oxidative metabolism during development is dependent on p53. 9,10 p53 can transactivate ribonucleotide reductase p53R2 (RRM2B) which is important for maintaining mtDNA in skeletal muscle. 11 Additionally, 2 recent studies have shown asso-

The Emerging Role of p53 in Exercise Metabolism

“…The enhanced p53 response with low carbohydrate (CHO) availability was also associated with enhanced acetyl CoA carboxylase (ACC) phosphorylation on serine 79 immediately postexercise (but not p38MAPK phosphorylation), thus suggesting that AMPK may be the dominant upstream signalling kinase regulating contractile-induced p53 phosphorylation. Interestingly, we also observed that SCO2 mRNA levels were not affected by exercise or CHO restriction (despite enhanced p53 activation), thus extending previous data from rodent muscle [15] that p53 may not regulate the SCO2 protein in skeletal muscle. It is worth noting, however, that our chosen biopsy sampling points were limited to immediately post-exercise and 3 h postexercise and hence it is possible that more detailed timecourse studies need to be performed to detect any significant effects of exercise on SCO2 expression.…”

“…In a subsequent study, Park et al [15] confirmed that loss of p53 reduces exercise capacity as they observed that maximal running time to exhaustion was reduced in p53 KO animals. During submaximal running exercise, blood lactate was also threefold higher in p53 KO mice compared with wild-type animals, thus demonstrating that energy production in vivo favours glycolytic metabolism.…”

“…As the so-called Guardian of the Genome, p53 is one of the most well-studied proteins in cell biology and its list of known functions include regulatory roles in cell cycle arrest, apoptosis, angiogenesis, DNA repair and cell senescence [13]. More recently, studies employing p53 knockout (KO) rodents provide convincing evidence for a regulatory role of p53 in modulating mitochondrial content and exercise performance [14][15][16]. Additionally, acute exercise also induces posttranslational modifications [16,17] and alterations in subcellular localisation [18], thereby consistent with the notion that p53 contributes to the regulatory network controlling contractile-induced mitochondrial biogenesis.…”

Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease

“…1). P53 has been reported to maintain mitochondrial biogenesis and performance in skeletal muscle (Saleem et al, 2009;Park et al, 2009).…”

Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high-fat diet restriction or change to a low-fat diet

“…The mean of the control group (HFD) was set as 1.0. The primer pair's sequences used were as follows: mitochondrial DNA (forward) 5 0 -CCGCA AGGGAAAGATGAAAGAC-3 0 and (reverse) 5 0 -TCGTTT GGTTTCGGGGTTTC-3 0 (Lagouge et al 2006); nucleic DNA (forward) 5 0 -CTTAGAGGGACAAGTGGCGTTC and (reverse) 5 0 -CGCTGAGCCAGTCAGTGTAG-3 0 (Park et al 2009). …”