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

Abstract

Sarcopenia, the loss of muscle mass and strength associated with age, has been linked to impairment of the cytosolic Ca 2+ peak that triggers muscle contraction, but mechanistic details remain unknown. Here we explore the hypothesis that a reduction in sarcoplasmic reticulum (SR) Ca 2+ concentration ([Ca 2+ ] SR) is at the origin of this loss of Ca 2+ homeostasis. We engineered Drosophila melanogaster to express the Ca 2+ indicator GAP3 targeted to muscle SR, and we developed a new method to calibrate the signal into [Ca 2+ ] SR in vivo. [Ca 2+ ] SR fell with age from ∼600 µM to 50 µM in close correlation with muscle function, which declined monotonically when [Ca 2+ ] SR was <400 µM. [Ca 2+ ] SR results from the pump-leak steady state at the SR membrane. However, changes in expression of the sarco/endoplasmic reticulum Ca 2+-ATPase (SERCA) pump and of the ryanodine receptor leak were too modest to explain the large changes seen in [Ca 2+ ] SR. Instead, these changes are compatible with increased leakiness through the ryanodine receptor as the main determinant of the [Ca 2+ ] SR decline in aging muscle. In contrast, there were no changes in endoplasmic reticulum [Ca 2+ ] with age in brain neurons. This article has an associated First Person interview with the first author of the paper.

Age-Related Skeletal Muscle Dysfunction Is Aggravated by Obesity: An Investigation of Contractile Function, Implications and Treatment

“…The age-related reduction in skeletal muscle function is multifactorial [ 23 ]. Some of the contributing factors are a reduction in the sarcoplasmic reticulum (SR) Ca 2+ concentration, dihydropyridine receptor–ryanodine receptor uncoupling (i.e., excitation–contraction uncoupling) and reduced sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) activity [ 43 , 82 , 83 ] that all have a negative impact on muscle activation and relaxation. A reduced myogenic capacity and an increase in catabolic agents [ 23 , 84 ] result in a reduction in contractile mass [ 52 , 53 , 54 ], particularly in fast fatigable muscle fibres [ 85 ].…”

Restoration of Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice

“…These changes result in ''leaky" RyRs with a higher probability of channel opening and leakage of Ca 2+ ions into the sarcoplasm, leading to reduced SR Ca 2+ reservoirs and muscle weakness [10]. Reduced SERCA activity also contributes to lower SR Ca 2+ stores, which compromises the amount of Ca 2+ released through RyR channels for contraction during muscle activation [11]. Accordingly, an age-related reduction in the SR Ca 2+ stores has been reported [11].…”

“…Reduced SERCA activity also contributes to lower SR Ca 2+ stores, which compromises the amount of Ca 2+ released through RyR channels for contraction during muscle activation [11]. Accordingly, an age-related reduction in the SR Ca 2+ stores has been reported [11]. These findings highlight the pivotal role of SR in the sarcopenia process and suggest that restoration of SERCA may be a promising intervention to counter muscle pathology in aging.…”

Animal models of sarcopenia

“…Lorenzo et al found that in Drosophila, there is a decrease in sarcoplasmic reticulum calcium with age that correlates with the decline in muscle function. They hypothesized that this decline was due to increased leakiness of the ryanodine receptor calcium channel allowing more calcium to leave the sarcoplasmic reticulum (Delrio‐Lorenzo, Rojo‐Ruiz, Alonso, & Garcia‐Sancho, 2020).…”