Effect of high-altitude exposure on skeletal muscle mitochondrial subcellular distribution, ultrastructure and respiration in sea-level residents

Endurance exercise performance is associated with a well-developed skeletal muscle mitochondrial network, which is composed of subsarcolemmal mitochondria interconnected with intermyofibrillar mitochondria bending around the myofibrils. High-altitude exposure is typically incorporated in elite sport training regimens, but little is known about how this network adapts to an environment characterised by tissue hypoxia. For this reason, we investigated how high-altitude exposure affects mitochondrial subcellular distribution, ultrastructure, respiratory control, and intrinsic mitochondrial respiratory capacity. Nine healthy and recreationally active sea-level residents (eight males and one female) resided at an altitude of 3454 m with biopsies collected from the vastus lateralis muscle before and after 7 and 28 days at high altitude. The muscular mitochondrial volume density ( MitoVD ) increased after high-altitude exposure, driven by an increase in the intermyofibrillar MitoVD . This was however accompanied by a decreased cristae surface area per skeletal muscle fibre volume ( MuscularCD ) because of a decline in the cristae surface area per mitochondrial volume ( MitoCD ). Despite a reduced MuscularCD , mass-specific maximal coupled respiration ( OXPHOS_CII+CI+ETF ) increased slightly, and was considerably elevated when normalised to MuscularCD , suggesting intrinsic adaptations to high altitude. The difference between cristae-specific OXPHOS_CII+CI+ETF and an associated cristae-specific leak respiration ( Leak_CII+CI+ETF ) indicated a markedly higher degree of coupling between the electron flow in the electron transport system and ATP production. As the effect size 95% confidence intervals includes trivial effects the results need to be substantiated. In conclusion, high-altitude exposure altered mitochondrial subcellular distribution, ultrastructure and induced intrinsic respiratory adaptations.