Sarcoplasmic reticulum Ca2+ decreases with age and correlates with the decline in muscle function in <i>Drosophila</i>

Abstract

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca²⁺ peak that triggers muscle contraction, but mechanistic details remain unknown. Here we explore the hypothesis that a reduction in sarcoplasmic reticulum (SR) Ca²⁺ concentration ([Ca²⁺]_SR) is at the origin of this loss of Ca²⁺ homeostasis. We engineered <i>Drosophila melanogaster</i> to express the Ca²⁺ indicator GAP3 targeted to muscle SR, and we developed a new method to calibrate the signal into [Ca²⁺]_SR<i>in vivo</i> [Ca²⁺]_SR fell with age from ∼600 µM to 50 µM in close correlation with muscle function, which declined monotonically when [Ca²⁺]_SR was <400 µM. [Ca²⁺]_SR results from the pump-leak steady state at the SR membrane. However, changes in expression of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump and of the ryanodine receptor leak were too modest to explain the large changes seen in [Ca²⁺]_SR Instead, these changes are compatible with increased leakiness through the ryanodine receptor as the main determinant of the [Ca²⁺]_SR decline in aging muscle. In contrast, there were no changes in endoplasmic reticulum [Ca²⁺] with age in brain neurons.This article has an associated First Person interview with the first author of the paper.