Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity

• Published in: Nature communications 2021-12, Vol.12 (1), p.7219-7219, Article 7219
• Main Authors: Zanou, Nadège, Dridi, Haikel, Reiken, Steven, Imamura de Lima, Tanes, Donnelly, Chris, De Marchi, Umberto, Ferrini, Manuele, Vidal, Jeremy, Sittenfeld, Leah, Feige, Jerome N., Garcia-Roves, Pablo M., Lopez-Mejia, Isabel C., Marks, Andrew R., Auwerx, Johan, Kayser, Bengt, Place, Nicolas
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 14/1; 14/19; 38; 38/88; 631/80/642/1463; 631/80/642/333/1465; 631/80/86/1999; 64; 64/60; 82/58; 82/80; Adaptation; Calcium (mitochondrial); Calcium (reticular); Calcium influx; Calcium ions; Congestive heart failure; Humanities and Social Sciences; Leak channels; Mitochondria; multidisciplinary; Muscle contraction; Muscles; Muscular function; Musculoskeletal system; Myotubes; NADH; Nicotinamide adenine dinucleotide; Oxidation; Oxidative phosphorylation; Phosphorylation; Proteins; Proteomics; Pyruvic acid; Receptors; Ryanodine receptors; Sarcoplasmic reticulum; Science; Science (multidisciplinary); Skeletal muscle; Training
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27422-1

Sustained ryanodine receptor (RyR) Ca 2+ leak is associated with pathological conditions such as heart failure or skeletal muscle weakness. We report that a single session of sprint interval training (SIT), but not of moderate intensity continuous training (MICT), triggers RyR1 protein oxidation and nitrosylation leading to calstabin1 dissociation in healthy human muscle and in in vitro SIT models (simulated SIT or S-SIT). This is accompanied by decreased sarcoplasmic reticulum Ca 2+ content, increased levels of mitochondrial oxidative phosphorylation proteins, supercomplex formation and enhanced NADH-linked mitochondrial respiratory capacity. Mechanistically, (S-)SIT increases mitochondrial Ca 2+ uptake in mouse myotubes and muscle fibres, and decreases pyruvate dehydrogenase phosphorylation in human muscle and mouse myotubes. Countering Ca 2+ leak or preventing mitochondrial Ca 2+ uptake blunts S-SIT-induced adaptations, a result supported by proteomic analyses. Here we show that triggering acute transient Ca 2+ leak through RyR1 in healthy muscle may contribute to the multiple health promoting benefits of exercise. Ryanodine receptor type 1 (RyR1) are involved in skeletal muscle contraction. Here, the authors show that a transient calcium leak in response to exercise-induced post translational modifications of RyR1 causes mitochondrial remodeling to improve respiration.