Role of SERCA Pump in Muscle Thermogenesis and Metabolism

Abstract

In muscle cells, the sarcoplasmic reticulum (SR) not only acts as a Ca2+ store, but also regulates the contractile characteristics of the muscle. Ca2+ release from the SR is the primary mechanism for activating muscle contraction and reuptake of Ca2+ by the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump causes muscle relaxation. The SERCA pump isoforms are encoded by three genes, SERCA 1, 2, and 3, which are differentially expressed in muscle and determine SR Ca2+ dynamics by affecting the rate and amount of Ca2+ uptake, thereby affecting SR store and release of Ca2+ in muscle. In muscle, small molecular weight proteins, including Phospholamban (PLB) and Sarcolipin (SLN), also regulate the SERCA pump. Regulation of the SERCA pump by PLB or SLN affects cytosolic Ca2+ dynamics and changes in cytosolic Ca2+ not only affect contractile function, but also mitochondrial ATP production. Recent studies have shown that alterations in cytosolic Ca2+ affects Ca2+ entry into mitochondria and ATP production; thus, Ca2+ serves as an integrating signal between muscle contraction-dependent energy demand and mitochondrial energy production. In addition, changes in cytosolic Ca2+ can affect Ca2+ signaling pathways modulating gene expression and muscle growth. An emerging area of research shows that SR Ca2+ cycling is also a player in muscle-based nonshivering thermogenesis. Recent data shows that SERCA uncoupling by SLN leads to increased ATP hydrolysis and heat production. Our studies, using genetically altered mouse models of SLN, show that SLN/SERCA interaction plays an important role in muscle thermogenesis and metabolism, which will be discussed here, in great length. © 2017 American Physiological Society. Compr Physiol 7:879-890, 2017.

Body temperature control in rats by muscle tone during rest or sleep

“…The importance of mitochondrial thermogenesis is uncertain because evidence has been reported both for [63][64][65] and against such thermogenesis. 67 The main evidence is impaired thermogenesis in mice with sarcolipin (Sln) knocked out, 24,25 Sln being a regulator of Serca. 67 The main evidence is impaired thermogenesis in mice with sarcolipin (Sln) knocked out, 24,25 Sln being a regulator of Serca.…”

“…27,66 The role of thermogenesis by "slippage" of Ca 2+ back into the cytosol at the site of Ca 2+ transport into SR by the ATPase Serca 25 also appears uncertain. 67 The main evidence is impaired thermogenesis in mice with sarcolipin (Sln) knocked out, 24,25 Sln being a regulator of Serca. Thus, Sln -/mice die within a few hours of exposure to 4°C if their interscapular BAT (iBAT) is also ablated, whereas iBAT ablation alone has no such effect.…”

“…[16][17][18][19][20] A representative statement is "more anaerobic muscles, high in type II fibers, tend to shiver in bursts whereas those relying more on aerobic metabolism, high in type I fibers, shiver more continuously". [23][24][25][26][27] Muscle tone has been described as resting mechanical and EMG activity and shown to increase significantly in resting human quadriceps muscles at ambient temperatures below 21.5°C by McKay et al, 28 who write: "An accepted model is that resting muscle is electrically and mechanically inactive at room temperature, that cooling provokes invisible microvibrations called thermoregulatory tonus, that severe cooling causes visible shivering, and that these are simply degrees of the same phenomenon (Blatteis et al, 2001; Haider and Lindsley 1964; Kleinebeckel and Klussman 1990)". By being included in the term shivering, muscle tone often goes unmentioned as a possible separate independent heat producing mechanism, as in a recent review of central control of body temperature 22 or in studies of NST in skeletal muscle.…”

“…By being included in the term shivering, muscle tone often goes unmentioned as a possible separate independent heat producing mechanism, as in a recent review of central control of body temperature 22 or in studies of NST in skeletal muscle. [23][24][25][26][27] Muscle tone has been described as resting mechanical and EMG activity and shown to increase significantly in resting human quadriceps muscles at ambient temperatures below 21.5°C by McKay et al, 28 who write: "An accepted model is that resting muscle is electrically and mechanically inactive at room temperature, that cooling provokes invisible microvibrations called thermoregulatory tonus, that severe cooling causes visible shivering, and that these are simply degrees of the same phenomenon (Blatteis et al, 2001; Haider and Lindsley 1964; Kleinebeckel and Klussman 1990)". But they also cite studies "showing that thermoregulatory muscle tone and cold shivering are independent forms of muscle activity with different regulating mechanisms (Konstantinov 1975; Meigal et al 1993; Petajan and Williams 1972)" and they postulate a model "whereby resting muscle mechanical activity is invoked first at ambient temperatures below thermoneutrality, whereas shivering is invoked as a last-resort response".…”

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

“…7 The majority of the energy expended by resting skeletal muscles is used to maintain the resting membrane potential and cytosolic [Ca 2+ ], through the action of the Na + -K + ATPase and the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA). 8 In mice, skeletal muscles' ATP consumption by the SERCA accounts for 40%-50% of the muscles' RMR or 12%-15% of the whole-body VO 2 . 9 In optimal conditions, SERCA harnesses the energy released by one ATP phosphate bond to translocate two Ca 2+ ions into the sarcoplasmic reticulum.…”