Sarcoplasmic reticulum Ca²⁺ decreases with age and correlates with the decline in muscle function in Drosophila

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 Drosophila melanogaster to express the Ca²⁺ indicator GAP3 targeted to muscle SR, and we developed a new method to calibrate the signal into [Ca²⁺]_SRin vivo [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.