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+](SR) in vivo. [Ca2+](SR) fell with age from similar to 600 mu M to 50 mu M in close correlation with muscle function, which declined monotonically when [Ca2+](SR) was <400 mu M. [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.