title: p53 improves aerobic exercise capacity and augments skeletal muscle mitochondrial DNA content.
abstract: BACKGROUND
  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.
  
  
  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 did not affect baseline cardiac function or inotropic reserve, we focused on the involvement of skeletal muscle and now report a wider role for p53 in modulating skeletal muscle mitochondrial function. p53 interacts with Mitochondrial Transcription Factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance, and regulates mtDNA content. The increased mtDNA in p53(+/+) compared to p53(-/-) mice was more marked in aerobic versus glycolytic skeletal muscle groups with no significant changes in cardiac tissue. These in vivo observations were further supported by in vitro studies showing overexpression of p53 in mouse myoblasts increases both TFAM and mtDNA levels whereas depletion of TFAM by shRNA decreases mtDNA content.
  
  
  CONCLUSIONS
  Our current findings indicate that p53 promotes aerobic metabolism and exercise capacity by using different mitochondrial genes and mechanisms in a tissue-specific manner.
authors.affiliation: Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md 20892, USA.
authors.forename: Joon-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Ping-Yuan
authors.initials: PY
authors.lastname: Wang
authors.forename: Takumi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Ho Joong
authors.initials: HJ
authors.lastname: Sung
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Ma
authors.forename: Jeong W
authors.initials: JW
authors.lastname: Choi
authors.forename: Stasia A
authors.initials: SA
authors.lastname: Anderson
authors.forename: Scot C
authors.initials: SC
authors.lastname: Leary
authors.forename: Robert S
authors.initials: RS
authors.lastname: Balaban
authors.forename: Ju-Gyeong
authors.initials: JG
authors.lastname: Kang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hwang
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017079:Exercise Tolerance / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism*; D009119:Muscle Contraction; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption; D005082:Physical Exertion; D034622:RNA Interference; D020218:Response Elements; D013550:Swimming; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D016277:Ventricular Function, Left
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse; D016159:Tumor Suppressor Protein p53
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