Abstract
The purpose of this study was to outline the timelines of mitochondrial function, oxidative stress and cytochrome c oxidase complex (COX) biogenesis in cardiac muscle with age, and to evaluate whether and how these age-related changes were attenuated by exercise. ICR/CD-1 mice were treated with pifithrin-μ (PFTμ), sacrificed and studied at different ages; ICR/CD-1 mice at younger or older ages were randomized to endurance treadmill running and sedentary conditions. The results showed that mRNA expression of p53 and its protein levels in mitochondria increased with age in cardiac muscle, accompanied by increased mitochondrial oxidative stress, reduced expression of COX subunits and assembly proteins, and decreased expression of most markers in mitochondrial biogenesis. Most of these age-related changes including p53 activity targeting cytochrome oxidase deficient homolog 2 (SCO2), p53 translocation to mitochondria and COX biogenesis were attenuated by exercise in older mice. PFTμ, an inhibitor blocking p53 translocation to mitochondria, increased COX biogenesis in older mice, but not in young mice. Our data suggest that physical exercise attenuates age-related changes in mitochondrial COX biogenesis and p53 activity targeting SCO2 and mitochondria, and thereby induces antisenescent and protective effects in cardiac muscle.
Highlights
Cardiac muscle undergoes a significant remodeling with age, and is mostly characterized by a significant loss of cardiac myocytes, reactive hypertrophy of the remaining cells and increased connective tissue
The main objective of this study was to find a correlative evidence that exercise would regulate oxidative stress and COX biogenesis via p53 activity targeting SCO2 and mitochondria, based on the fundamental role of p53 in reactive oxygen species (ROS) homeostasis and mitochondrial biogenesis
This study has generated three additional lines of information regarding the effects of exercise on p53 expression and COX biogenesis in cardiac muscle, and proposed a novel correlation that p53 activity may be implicated in exerciseinduced cardiac COX biogenesis
Summary
Cardiac muscle undergoes a significant remodeling with age, and is mostly characterized by a significant loss of cardiac myocytes, reactive hypertrophy of the remaining cells and increased connective tissue. Mitochondrial reticulum was dynamic, sensitive and plastic in response to oxidative stress [2], mitochondria contributed to cardiac dysfunction and myocyte apoptosis via a loss of metabolic capacity and by the production and release of reactive oxygen species (ROS) [3]. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA(mtDNA) mutations and deletions, increased mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, decreased cardiac sarco(endo)plasmic reticulum Ca2+-ATPase(SERCA2) protein, and activation of the calcineurin-nuclear factor of activated T-cell pathway. All of these changes with age are attenuated by overexpressing catalase targeted to mitochondria [4,5]. The application of mitochondrial antioxidants or nutrients is hoped to delay cardiac aging, prevent ROS-related cardiovascular diseases, diabetes, Alzheimers’ disease, immune dysfunction, and prolong median lifespan of people [6,7,8]
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