Sarcoplasmic reticulum Ca 2+ 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.