Skeletal muscle is the largest organ in the body, contributing close to 40% of total body mass. It plays a major role in metabolism and key physiological and biochemical processes in addition to its critical functions of force generation and movement [25]. Contractile force generation is a process mediated by calcium ions resulting in the activation of interaction between myosin and actin filaments [30]. As a result, the regulation of calcium homeostasis is critical to proper maintenance of muscle function. A key regulator of cellular calcium homeostasis is the Sarcoendoplasmic Reticulum Calcium ATPase (SERCA) pump which acts to transport calcium ions from the cytosol back to the sarcoplasmic reticulum (SR) following muscle contraction. The SERCA protein is localized on the SR membrane and has been reported to be the most abundant protein in the SR [6].
The SERCA pumps belong to the family of P-type ATPases that includes a series of membrane-bound ATPases, such as plasma membrane Ca2+ ATPase (PMCA), Na+/K+ ATPase, and H+/K+ ATPase [64]. A common feature of these P-type ATPases is to transport metal ions against the gradient across the SR membrane coupled with the hydrolysis from ATP to ADP [47, 48]. As illustrated in Fig. 1, the primary function of SERCA is the uptake of cytosolic Ca2+ back into SR lumen using energy derived from the hydrolysis of ATP. This allows the maintenance of the cytosolic Ca2+ concentration at low levels between 50 and 100 nM [5]. Figure 2 shows the structure of the SERCA pump as reported by Watson in 2015 [69], revealing a globular lobe that protrudes into the cytosol connecting with the SR membrane through a stalk that has only a minor extension into the lumen of the SR [5].
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During excitation-contraction (E-C) coupling events associated with muscle force generation, Ca2+ ions are released through the ryanodine receptor (RyR) channels in the SR membrane increasing the cytosolic [Ca2+] to 1-2 μM for a few milliseconds. This high concentration of Ca2+ ions facilitates the interaction of calcium with troponin to trigger the sequence of events leading to force production [33]. However, prolonged high cytosolic [Ca2+] can be detrimental to cellular homeostasis, stimulating calcium signaling pathways and leading to activation of proteases such as calpains [44] and matrix metalloproteinases (MMPs) that can degrade cellular components [58]. Moreover, calcium ions can directly control contractile function in muscles, especially in cardiac muscle, where the intracellular calcium release from the SR is triggered by a small influx of calcium, which is termed as calcium-induced calcium release (CICR). Elevated dysregulated calcium concentration can directly contribute to adverse cardiac remodeling and disruption of systolic and diastolic function [36]. Thus, dysfunctional SERCA pumps could contribute to high cytosolic calcium, limiting not only muscle function, but also causing impairments in cellular metabolism and function.
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.
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