P53 Regulation of Cellular Homeostasis in Skeletal Muscle with Training: An Evaluation of Two Mouse Models

The tumour suppressor protein p53, well‐known for its ability to mediate oxidative stress, plays an essential role in maintaining cellular homeostasis. This is accomplished through enhanced antioxidant enzyme transcription and cellular senescence with low to moderate levels of stress, or through increased apoptosis and the induction of cell death with greater levels of stress. However, recent literature has dictated a novel role for p53, dependent on its subcellular localization. With certain stressors such as exercise, phosphorylation of p53 at specific residues allows for enhanced mitochondrial localization whereby it functions to maintain mitochondrial DNA integrity, thus leading to enhanced oxidative metabolism. It is evident that understanding the effects of chronic exercise on p53 localization, and the regulation of p53‐dependent signaling pathways (autophagy, antioxidant capacity, and mitochondrial biogenesis) is essential for a full comprehension of how exercise affects muscle health. To study this further, two mouse models were compared to assess the role of p53 in mediating muscle phenotype, mitochondrial function and endurance performance. Whole body (WB) C57BL/6J p53 wild‐type (WT) and knockout (KO) mice, as well as MCK‐driven p53 muscle‐specific (MS) KO were used. All mice underwent a 6‐week progressive treadmill training protocol with concomitant pre‐ and post‐endurance stress tests to observe training adaptations. Phenotypic analyses confirmed matched body weight in KO and WT mice within both mouse models. Slight elevations in body mass were observed within MS mice relative to WB mice independent of genotype, with no observable effect of training. However, training did reduce epididymal fat mass in both groups. Tissue‐specific analysis revealed increased gastrocnemius mass corrected for body mass in WB KO relative to WT mice, however this phenotypic adaptation was not apparent in the MS mice. COX enzyme activity, a predictor of mitochondrial content, increased in WB mice, but this adaptation was not apparent MS mice. To delineate the effects of p53 on aerobic metabolism, respiration analyses confirmed increased state 3 respiration in WB WT mice with training, however this trend was not observed in the WB KO group, or in MS KO mice. Additionally, reduced state 3 respiration was observed in the WB mice relative to the MS mice. Mitochondrial reactive oxygen species (ROS) emission was elevated in both WB and MS mice, but training restored ROS levels to normal. Pre‐training exercise performance was similar between the WB WT and KO groups, as well as the MS WT mice, however MS KO distances were significantly decreased, concomitant with moderately elevated lactate levels. However, training effectively restored MS KO running distances to normal levels, although this was less pronounced than seen in the WB KO mice. Thus, whole body (WB) and muscle specific (MS) p53 knockout animals display largely similar phenotypic characteristics and adaptations to training, and provide equally useful experimental models for the investigation of the role of p53 in muscle function and metabolism. Support or Funding Information This work is supported by the Natural Science and Engineering Research Council (NSERC) of Canada.

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