The major tumour suppressor protein, p53, is one of the most well-studied 
proteins in cell biology. Often referred to as the Guardian of the Genome, the 
list of known functions of p53 include regulatory roles in cell cycle arrest, 
apoptosis, angiogenesis, DNA repair and cell senescence. More recently, p53 has 
been implicated as a key molecular player regulating substrate metabolism and 
exercise-induced mitochondrial biogenesis in skeletal muscle. In this context, 
the study of p53 therefore has obvious implications for both human health and 
performance, given that impaired mitochondrial content and function is 
associated with the pathology of many metabolic disorders such as ageing, type 2 
diabetes, obesity and cancer, as well as reduced exercise performance. Studies 
on p53 knockout (KO) mice collectively demonstrate that ablation of p53 content 
reduces intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondrial yield, 
reduces cytochrome c oxidase (COX) activity and peroxisome 
proliferator-activated receptor gamma co-activator 1-α protein content whilst 
also reducing mitochondrial respiration and increasing reactive oxygen species 
production during state 3 respiration in IMF mitochondria. Additionally, p53 KO 
mice exhibit marked reductions in exercise capacity (in the magnitude of 50 %) 
during fatiguing swimming, treadmill running and electrical stimulation 
protocols. p53 may regulate contractile-induced increases in mitochondrial 
content via modulating mitochondrial transcription factor A (Tfam) content 
and/or activity, given that p53 KO mice display reduced skeletal muscle 
mitochondrial DNA, Tfam messenger RNA and protein levels. Furthermore, upon 
muscle contraction, p53 is phosphorylated on serine 15 and subsequently 
translocates to the mitochondria where it forms a complex with Tfam to modulate 
expression of mitochondrial-encoded subunits of the COX complex. In human 
skeletal muscle, the exercise-induced phosphorylation of p53(Ser15) is enhanced 
in conditions of reduced carbohydrate availability in association with enhanced 
upstream signalling through 5'adenosine monophosphate-activated protein kinase 
but not p38 mitogen-activated protein kinase. In this way, undertaking regular 
exercise in carbohydrate restricted states may therefore be a practical approach 
to achieve the physiological benefits of consistent p53 signalling. Although our 
knowledge of p53 in exercise metabolism has advanced considerably, much of our 
current understanding of p53 regulation and associated targets is derived from 
various non-muscle cells and tissues. As such, many fundamental questions remain 
unanswered in contracting skeletal muscle. Detailed studies concerning the 
time-course of p53 activation (including additional post-translational 
modifications and subsequent subcellular translocation), as well as the effects 
of exercise modality (endurance versus resistance), intensity, duration, fibre 
type, age, training status and nutrient availability, must now be performed so 
that we can optimise exercise prescription guidelines to strategically target 
p53 signalling. The emerging role of p53 in skeletal muscle metabolism therefore 
represents a novel and exciting research area for exercise and muscle 
physiologists.