Nat Commun.: co-auth.: I.Lopez-Mejia

Nat Commun. 2021 Dec 10;12(1):7219. doi: 10.1038/s41467-021-27422-1.

Acute RyR1 Ca 2+ leak enhances NADH-linked mitochondrial respiratory capacity

Nadège Zanou 1Haikel Dridi 2Steven Reiken 2Tanes Imamura de Lima 3Chris Donnelly 4Umberto De Marchi 5Manuele Ferrini 4Jeremy Vidal 4Leah Sittenfeld 2Jerome N Feige 5 6Pablo M Garcia-Roves 7Isabel C Lopez-Mejia 8Andrew R Marks 2 9Johan Auwerx 3Bengt Kayser 4Nicolas Place 10


Sustained ryanodine receptor (RyR) Ca2+ 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 Ca2+ content, increased levels of mitochondrial oxidative phosphorylation proteins, supercomplex formation and enhanced NADH-linked mitochondrial respiratory capacity. Mechanistically, (S-)SIT increases mitochondrial Ca2+ uptake in mouse myotubes and muscle fibres, and decreases pyruvate dehydrogenase phosphorylation in human muscle and mouse myotubes. Countering Ca2+ leak or preventing mitochondrial Ca2+ uptake blunts S-SIT-induced adaptations, a result supported by proteomic analyses. Here we show that triggering acute transient Ca2+ leak through RyR1 in healthy muscle may contribute to the multiple health promoting benefits of exercise.