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

## TL;DR

MCARE is a muscle protein that helps control calcium levels, and its absence causes muscle weakness and damage in mice.

## Contribution

MCARE is newly identified as a regulator of SERCA1 activity in fast-twitch muscle through competitive inhibition of myoregulin.

## Key findings

- MCARE enhances SERCA1 activity by inhibiting myoregulin in fast-twitch muscle.
- Mcare-deficient mice show progressive muscle wasting and exercise-induced damage.
- MCARE is essential for calcium homeostasis and muscle function in fast-twitch fibers.

## Abstract

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.

The study reveals that MCARE, a previously uncharacterized muscle protein, controls calcium handling and contraction in skeletal muscle, and its absence leads to impaired muscle function in mice.