Contractile In/Activity Influence Mitochondrial Morphology and Membrane Interactions in Mouse Skeletal Muscle

Abstract

Dynamic changes in mitochondrial morphology regulate mitochondrial function and contribute to cellular function and adaptation in vitro, particularly in response to fluctuations in the metabolic status (energy supply vs demand). However, in skeletal muscle where the metabolic status fluctuates during exercise and disuse, whether mitochondrial morphology is actively remodeled is unclear. To investigate this question, the metabolic state was manipulated in the mouse by either i) a single 3‐hour bout of voluntary exercise on running wheel, or ii) an acute disuse model consisting of 6 hours of mechanical ventilation to unload the diaphragm. We quantified changes in both subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial morphology and membrane interactions with a new method combining scanning (SEM) and transmission electron microscopy (TEM) in two orthogonal planes. Exercise depleted intramyocellular lipid droplets whereas diaphragm inactivity caused their accumulation (P<0.01). Immediately after exercise, the number of electron‐dense contact sites connecting adjacent mitochondria in the soleus was increased by 110% for SS (P<0.05) and 200% for IMF (P<0.01), and the number of continuous IMF mitochondria across Z‐lines doubled (P<0.01). In contrast, the inactive diaphragm contained more small (P<0.05), rounded (P<0.05) and granular (P<0.05) IMF mitochondria, along with numerous autophagosomes, indicating mitochondrial fragmentation. Thus, consistent with in vitro paradigms, skeletal muscle mitochondrial morphology and membrane interactions are remodeled by the metabolic status during contractile in/activity. Work funded by the Wellcome Trust and CIHR.