Abstract
p53 plays an important role in regulating mitochondrial homeostasis. However, it is unknown whether p53 is required for the physiological and mitochondrial adaptations with exercise training. Furthermore, it is also unknown whether impairments in the absence of p53 are a result of its loss in skeletal muscle, or a secondary effect due to its deletion in alternative tissues. Thus, we investigated the role of p53 in regulating mitochondria both basally, and under the influence of exercise, by subjecting C57Bl/6J whole-body (WB) and muscle-specific p53 knockout (mKO) mice to a 6-week training program. Our results confirm that p53 is important for regulating mitochondrial content and function, as well as proteins within the autophagy and apoptosis pathways. Despite an increased proportion of phosphorylated p53 (Ser15) in the mitochondria, p53 is not required for training-induced adaptations in exercise capacity or mitochondrial content and function. In comparing mouse models, similar directional alterations were observed in basal and exercise-induced signaling modifications in WB and mKO mice, however the magnitude of change was less pronounced in the mKO mice. Our data suggest that p53 is required for basal mitochondrial maintenance in skeletal muscle, but is not required for the adaptive responses to exercise training.
Highlights
P53 is known to play a role in regulating additional mitochondrial-dependent signaling pathways, including autophagy/mitophagy and apoptosis
Required for the regulation of ubiquitination[6]. It has not been established how the autophagy pathway is regulated by p53 with exercise training. p53 is well-known for its role in regulating apoptosis, since it can transcriptionally regulate numerous pro-apoptotic genes including Bax and Bid to induce DNA fragmentation[4,18,19]
Exercise-induced p53 localization to the nucleus is reduced with training and increases in the mitochondria. p53 protein expression in whole muscle and subcellular compartments was examined following acute exercise in both trained and untrained WT mice
Summary
P53 is known to play a role in regulating additional mitochondrial-dependent signaling pathways, including autophagy/mitophagy and apoptosis. Required for the regulation of ubiquitination[6] It has not been established how the autophagy pathway is regulated by p53 with exercise training. Literature published on the role of p53 in regulating autophagy, apoptosis, mitochondrial biogenesis and metabolism, have been established largely through the use of a whole body p53 knockout model. Though this research has elucidated novel roles for p53, recently published work utilizing a muscle-specific p53 knockout model did not observe any reductions in mitochondrial content or the expression of nuclear genes encoding mitochondrial proteins[24,25]. The purpose of this study was to elucidate the role of p53 in regulating skeletal muscle adaptations to endurance training, related to the mitochondrial biogenesis, autophagy, and apoptosis pathways. We utilized a muscle-specific p53 deficient mouse and when relevant, compared this model to traditionally employed p53 whole body knockout animals under identical endurance training stimuli
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