MCARE enhances SERCA1 activity in fast-twitch muscle to maintain calcium handling and muscle integrity

The release of Ca²⁺ from the sarcoplasmic reticulum into the cytoplasm, followed by its reuptake by sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA), is critical for the muscle contraction-relaxation cycle. In this study, we identify a small transmembrane protein, predominantly expressed in fast-twitch muscles, which regulates SERCA1 activity. This protein, termed muscle-enriched Ca²⁺ regulator (MCARE), enhances SERCA1 function by competitively inhibiting myoregulin, a muscle-specific micropeptide that otherwise suppresses SERCA1 activity. By facilitating more efficient Ca²⁺ clearance from the cytoplasm, MCARE accelerates muscle relaxation. Mcare-deficient mice exhibit symptoms resembling muscular dystrophy, including progressive muscle wasting in fast-twitch muscles, reduced muscle strength, and increased susceptibility to exercise-induced muscle damage. Notably, these mice also present with distinctive rippling muscle contractions. Our findings establish MCARE as a key regulator of SERCA1 activity, essential for maintaining Ca²⁺ homeostasis and the functional integrity of fast-twitch muscle fibers.