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  • Title: Redox modification of ryanodine receptor contributes to impaired Ca2+ homeostasis and exacerbates muscle atrophy under high altitude.
    Author: Agrawal A, Rathor R, Kumar R, Suryakumar G, Singh SN, Kumar B.
    Journal: Free Radic Biol Med; 2020 Nov 20; 160():643-656. PubMed ID: 32916280.
    Abstract:
    At extreme altitude, prolonged and severe hypoxia menaces human function and survival, and also associated with profound loss of muscle mass which results into a debilitating critical illness of skeletal muscle atrophy. Hypobaric hypoxia altered redox homeostasis and impaired calcium ion handling in skeletal muscles. Dysregulated Ca2+ homeostasis and activated calpain is the prime stressor in high altitude hypoxia while the reason for subsequent abnormal release of pathological Ca2+ into cytoplasm is largely unexplored. The present study identified the redox remodeling in the Ca2+ release channel, Ryanodine Receptor (RyR1) owing to its hypernitrosylation state in skeletal muscles in chronic hypobaric hypoxia exposed rats. RyR1-hypernitrosylation decreases the binding of FKBP12/calstabin-1 and other complexes from the channel, causing "leakiness" in RyR1 ion-channel. A strong RyR1 stabilizer, S107 enhanced binding affinity of FKBP12 with hypernitrosylated RyR1, reduced Sarco(endo)plasmic reticulum (SR) Ca2+ leak and improved muscle strength and function under chronic hypoxia. Administration of S107 inhibited the skeletal muscle damage, maintained ultrastructure of sarcomere and sarcolemmal integrity. Histological analysis proved the increase in cross-sectional area of myofibers. Further, the number of apoptotic cells was also reduced by S107 treatment. Conclusively, we proposed that the redox remodeling of RyR1 (hypernitrosylated-RyR1) might be responsible for dysregulated Ca2+ homeostasis which consequently impaired muscle strength and function in response to chronic hypoxic stress. Reduced SR Ca2+ leak and enhanced binding affinity of FKBP12 may provide a novel therapeutic avenue in ameliorating skeletal muscle atrophy at high altitude.
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