Apoptotic susceptibility, muscle and mitochondrial perturbations in skeletal muscle of p53 wild‐type (WT) and knockout (KO) mice

Abstract

Evidence indicates that p53 plays a role in modulating apoptosis, cell‐cycle arrest and aerobic metabolism. Our goal was to evaluate the role of p53 in regulating basal and exercise‐induced apoptosis in skeletal muscle. p53 KO mice had impaired whole muscle cytochrome c oxidase (COX) activity and reduced intermyofibrillar (IMF) state 3 respiration. The rate of reactive oxygen species (ROS) production during state 3 was ∼75% higher in subsarcolemmal (SS) mitochondria and ∼ 2‐fold higher in IMF mitochondria in KO mice. Despite this, KO mice had a 46% lower maximum speed (Vmax) of mitochondrial permeability transition pore (mtPTP) opening and a 19% greater time to Vmax in SS mitochondria. There were no changes in pore kinetics in the IMF mitochondria. However, a ∼2‐fold decrease in basal cytochrome c release in the IMF mitochondria in p53 KO mice was detected. Surprisingly, muscle weight / gram of body weight was 1.7‐fold higher in KO, compared to the WT animals. p53 KO mice that were endurance trained for eight weeks on a running wheel ran ∼5‐fold lower distances than the WT mice, and exhibited a trend towards decreased ROS production in the SS mitochondria. Muscle fatigue, evaluated using in situ muscle contraction, was also greater in KO animals. These data indicate that lack of p53 impairs mitochondrial function, endurance capacity and reduces apoptotic potential in skeletal muscle.