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

Nadège Zanou (), Haikel Dridi, Steven Reiken, Tanes Imamura de Lima, Chris Donnelly, Umberto De Marchi, Manuele Ferrini, Jeremy Vidal, Leah Sittenfeld, Jerome N. Feige, Pablo M. Garcia-Roves, Isabel C. Lopez-Mejia, Andrew R. Marks, Johan Auwerx, Bengt Kayser and Nicolas Place ()
Additional contact information
Nadège Zanou: University of Lausanne
Haikel Dridi: Columbia University Vagelos College of Physicians and Surgeons
Steven Reiken: Columbia University Vagelos College of Physicians and Surgeons
Tanes Imamura de Lima: École Polytechnique Fédérale de Lausanne (EPFL)
Chris Donnelly: University of Lausanne
Umberto De Marchi: Nestlé Research – École Polytechnique Fédérale de Lausanne (EPFL)
Manuele Ferrini: University of Lausanne
Jeremy Vidal: University of Lausanne
Leah Sittenfeld: Columbia University Vagelos College of Physicians and Surgeons
Jerome N. Feige: Nestlé Research – École Polytechnique Fédérale de Lausanne (EPFL)
Pablo M. Garcia-Roves: L’Hospitalet del Llobregat
Isabel C. Lopez-Mejia: University of Lausanne
Andrew R. Marks: Columbia University Vagelos College of Physicians and Surgeons
Johan Auwerx: École Polytechnique Fédérale de Lausanne (EPFL)
Bengt Kayser: University of Lausanne
Nicolas Place: University of Lausanne

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27422-1

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