Simulated altitude is medicine: intermittent exposure to hypobaric hypoxia and cold accelerates injured skeletal muscle recovery

Abstract

Muscle injuries are the leading cause of sports casualties. Because of its high plasticity, skeletal muscle can respond to different stimuli to maintain and improve functionality. Intermittent hypobaric hypoxia (IHH) improves muscle oxygen delivery and utilization. Hypobaria coexists with cold in the biosphere, opening the possibility to consider the combined use of both environmental factors to achieve beneficial physiological adjustments. We studied the effects of IHH and cold exposure, separately and simultaneously, on muscle regeneration. Adult male rats were surgically injured in one gastrocnemius and randomly assigned to the following groups: (1) CTRL: passive recovery; (2) COLD: intermittently exposed to cold (4°C); (3) HYPO: submitted to IHH (4500 m); (4) COHY: exposed to intermittent simultaneous cold and hypoxia. Animals were subjected to these interventions for 4 h/day for 9 or 21 days. COLD and COHY rats showed faster muscle regeneration than CTRL, evidenced after 9 days at histological (dMHC-positive and centrally nucleated fibre reduction) and functional levels after 21 days. HYPO rats showed a full recovery from injury (at histological and functional levels) after 9 days, while COLD and COHY needed more time to induce a total functional recovery. IHH can be postulated as an anti-fibrotic treatment since it reduces collagen I deposition. The increase in the pSer473Akt/total Akt ratio observed after 9 days in COLD, HYPO and COHY, together with the increase in the pThr172AMPKα/total AMPKα ratio observed in the gastrocnemius of HYPO, provides clues to the molecular mechanisms involved in the improved muscle regeneration. KEY POINTS: Only intermittent hypobaric exposure accelerated muscle recovery as early as 9 days following injury at histological and functional levels. Injured muscles from animals treated with intermittent (4 h/day) cold, hypobaric hypoxia or a simultaneous combination of both stimuli regenerated histological structure and recovered muscle function 21 days after injury. The combination of cold and hypoxia showed a blunting effect as compared to hypoxia alone in the time course of the muscle recovery. The increased expression of the phosphorylated forms of Akt observed in all experimental groups could participate in the molecular cascade of events leading to a faster regeneration. The elevated levels of phosphorylated AMPKα in the HYPO group could play a key role in the modulation of the inflammatory response during the first steps of the muscle regeneration process.

Keywords: AKT; AMPK; mTOR; muscle function; muscle histology; muscle injury; regeneration.