Abstract
As a key regulator of cellular calcium homeostasis, the Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) pump acts to transport calcium ions from the cytosol back to the sarcoplasmic reticulum (SR) following muscle contraction. SERCA function is closely associated with muscle health and function, and SERCA activity is susceptible to muscle pathogenesis. For example, it has been well reported that pathological conditions associated with aging, neurodegeneration, and muscular dystrophy (MD) significantly depress SERCA function with the potential to impair intracellular calcium homeostasis and further contribute to muscle atrophy and weakness. As a result, targeting SERCA activity has attracted attention as a therapeutical method for the treatment of muscle pathologies. The interventions include activation of SERCA activity and genetic overexpression of SERCA. This review will focus on SERCA function and regulation mechanisms and describe how those mechanisms are affected under muscle pathological conditions including elevated oxidative stress induced by aging, muscle disease, or neuromuscular disorders. We also discuss the current progress and therapeutic approaches to targeting SERCA in vivo.
Highlights
As a key regulator of cellular calcium homeostasis, the Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) pump acts to transport calcium ions from the cytosol back to the sarcoplasmic reticulum (SR) following muscle contraction
The primary goal of this review is to provide an overview of the impact of pathological conditions such as high oxidative stress induced by aging, muscle disease or neuromuscular disorders on SERCA function, and the potential therapeutic approaches via targeting SERCA
We tested the effectiveness of CDN1163 as an intervention to restoring the impaired SERCA function, and we reported in muscle of the CuZnSOD knock out (Sod1KO) mice
Summary
SERCA 1a, 1b*, 2a, 2b (*fetal only) SERCA 2a, 2b SERCA 2a, 2b SERCA 2b, 3a, 3b, 3c is found to be expressed in all muscle types, but primarily interacts with the SERCA 2a isoform in cardiac and slowtwitch muscles. Our group reported previously that SERCA activity was impaired in skeletal muscle in a mouse model of high oxidative stress in response to a lack of CuZnSOD (Sod1KO) This is a genetically modified mouse model that exhibits a number of accelerated aging phenotypes including muscle atrophy and weakness [54]. In response to oxidative inactivation of SERCA function, the calcium regulation in skeletal muscles may be impaired resulting in an elevated cytosolic Ca2+ concentration. This in turn has been reported to be detrimental to the excitation-contraction coupling (E-C coupling) system, as this system highly relies on the stable Ca2+ homeostasis balancing the Ca2+ release from ryanodine receptors (RyRs) during the contraction and the re-uptaking by SERCA during the relaxation [3, 7]. While this study is still preliminary and the longterm effects remain to be determined, these results open a new field of research and new therapeutic avenues for neuromuscular disease in aging
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