RESUMEN
Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wild-type mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.
Asunto(s)
ADN Mitocondrial , Proteína p53 Supresora de Tumor , Animales , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Células Endoteliales/metabolismo , Ratones , Actividad Motora , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: The purpose of this study was to determine the degree to which subtalar joint pronation resulting from a supple planus foot affects knee alignment, hip muscle activation and ground reaction force attenuation in female athletes during a broad jump-to-cut maneuver. METHODS: Twelve National Collegiate Athletic Association (NCAA) Division II female soccer players (age=19.4±1.4 years, height=1.64±0.05 m, mass=64.10±4.8 kg) were identified as having either supple planus (SP) or rigid feet (RF). Participants completed three broad jump-to-cut trials onto a force plate while EMG and motion data were collected. Muscle activation levels (percentage of maximal voluntary contraction [%MVC]) in the gluteus maximus, gluteus medius, biceps femoris, and rectus femoris were calculated, and peak vertical and medial shear force, rate of loading, and valgus angle were collected for each trial. RESULTS: Mann-Whitney U tests revealed no statistical significance between foot-type groups, however, effect size statistics revealed practical significance for between-group %MVC biceps femoris (d=1.107), %MVC gluteus maximus (d=1.069), and vertical ground reaction force (d=1.061). CONCLUSIONS: Athletes with a SP foot type may experience decreased hip muscle activation associated with increased vertical ground reaction force during a broad jump-to-cut maneuver. This might result in reduced dynamic stability and neuromuscular control during deceleration, potentially increasing the risk of non-contact ACL injury in female soccer players.