Role of p53 Within the Regulatory Network Controlling Muscle Mitochondrial Biogenesis Ayesha Saleem 1,2 , Heather N. Carter 1,2 , Sobia Iqbal 1,2 , and David A. Hood 1,2,3 1 School of Kinesiology and Health Science, 2 Muscle Health Research Centre, and 3 Department of Biology, York University, Toronto, Ontario, Canada SALEEM, A., H.N. CARTER, S. IQBAL, and D.A. HOOD. Role of p53 within the regulatory network controlling muscle mitochondrial biogenesis. Exerc. Sport Sci. Rev., Vol. 39, No. 4, pp. 199Y205, 2011. The tumor suppressor protein p53 is recognized to contribute significantly to the regulation of mitochondrial content. Mice without p53 have reduced endurance capacity and muscle performance. However, the function of p53 in muscle remains to be fully established. Understanding how p53 coordinates mitochondrial homeostasis will facilitate a better comprehension of how exercise could constitute as a therapy for cancer treatment. Key Words: exercise, gene expression, PGC-1>, mTOR, autophagy, fission/fusion INTRODUCTION As the incidence and prevalence of cancer increases, the costs associated with the care, treatment, and management of cancer and associated comorbidities continue to surge. It is imperative that the molecular biology and pathology of cancer is studied to fine-tune potential therapeutic strategies available for tumor treatment. The powerful apoptogenic and growth-suppressive activity of the tumor suppressor protein p53, coupled with the fact that p53 is inactivated or mutated in 50% of all tumors, make it an attractive target for cancer therapeutics. The activation of p53 is an established event orchestrated by the cell in response to a stress signal. Once activated, p53 mounts a reactive response to the imposed insult by inducing cell cycle arrest and facilitating DNA repair or, in the case of irreparable damage, by promoting cell death or apoptosis (17). Emerging evidence indicates that p53 also executes an adap- tive response to metabolic stress by controlling oxidative metabolism (20). Because it commonly is accepted that met- abolic perturbations are a hallmark of cancer progression, the p53-mediated regulation of energy metabolism is being stud- ied as a possible therapeutic modality in cancer treatment and management. Endurance exercise is one of the best possible means avail- able to modulate whole body metabolism. In addition to im- proving metabolic performance, a plethora of short-term and longitudinal studies have shown that regular physical activity extends life expectancy and reduces morbidity. Elucidating the underlying causes and molecular signaling events, such as the role of p53 in the adaptive response to endurance exer- cise, carries great significance for the treatment of physical inactivity-related and impaired metabolism-related diseases such as obesity, insulin resistance, type 2 diabetes, cancer, and car- diovascular diseases that overburden our health care systems. Here, we hypothesize that p53 and its activation (26) are involved in the complex network of transcriptional (12,13,31) and posttranscriptional events underlying exercise-mediated adaptations in mitochondrial synthesis (Fig. 1) that work in concert to orchestrate improvements in oxidative metabo- lism. We also summarize the known conduits by which p53 contributes to this process and allude to directions for future research that could further implicate p53 as a vital player in the regulatory network controlling muscle mitochondrial biogenesis. OVERVIEW OF EXERCISE-INDUCED MITOCHONDRIAL BIOGENESIS A highly malleable tissue, skeletal muscle exhibits a re- markable range of plasticity in response to a number of phys- iological and pathophysiological stimuli. With endurance exercise training, there is a change in substrate metabolism, an increase in mitochondrial content, and an improved exercise tolerance. Since this first was noted many years ago (11), many 199 ARTICLE Address for correspondence: David A. Hood, Ph.D., School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Ontario, M3J 1P3, Canada (E-mail: dhood@yorku.ca). Accepted for publication: July 11, 2011. Associate Editor: LaDora V. Thompson, Ph.D. 0091-6331/3904/199Y205 Exercise and Sport Sciences Reviews Copyright * 2011 by the American College of Sports Medicine Copyright © 2011 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.