Sarcolipin: A Key Thermogenic and Metabolic Regulator in Skeletal Muscle

Abstract

Skeletal muscle constitutes ∼40% of body mass and has the capacity to play a major role as thermogenic, metabolic, and endocrine organ. In addition to shivering, muscle also contributes to nonshivering thermogenesis via futile sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA) activity. Sarcolipin (SLN), a regulator of SERCA activity in muscle, plays an important role in regulating muscle thermogenesis and metabolism. Uncoupling of SERCA by SLN increases ATP hydrolysis and heat production, and contributes to temperature homeostasis. SLN also affects whole-body metabolism and weight gain in mice, and is upregulated in various muscle diseases including muscular dystrophy, suggesting a role for SLN during increased metabolic demand. In this review we also highlight the physiological roles of skeletal muscle beyond contraction.

Keywords: SERCA; metabolism; sarcolipin; skeletal muscle; thermogenesis.

Figure 1. Skeletal muscle also serves as an important thermogenic, metabolic and endocrine organ

Skeletal muscle is involved in both shivering and nonshivering thermogenic mechanisms, which are recruited during cold adaptation and facultative diet induced thermogenesis (fDIT). Skeletal muscle also serves as an endocrine organ by secreting several myokines to communicate with other participating organs (BAT, WAT, Liver and Brain) to maintain energy homeostasis under different metabolic and patho-physiological stress conditions, including exercise, inflammation and muscle disease. Exercise induced increase in energy expenditure has been shown to be beneficial in treating metabolic disorders. Crosstalk between adipose tissues and skeletal muscle through adipokines and myokines facilitate metabolic homeostasis. Neuro-hormonal input from the central nervous system plays a central role in coordinating muscle physiology and metabolism. WAT- White Adipose Tissue, BAT- Brown Adipose Tissue

Figure 2. Sarcolipin promotes oxidative metabolism under conditions of increased energy demand

During muscle contraction, membrane depolarization leads to activation of DHPR/RYR1 complex leading to release of Ca²⁺ from the SR. As the cytosolic Ca²⁺ concentration rises, it binds to myofilaments and triggers muscle contraction. Elevated cytosolic Ca²⁺ activates SERCA which pumps Ca²⁺ back into the SR. The energy demand during normal activity (routine functions) is relatively low. On the other hand, many different patho-physiological states increase energy demand in muscle. In addition, several cytokines and neuro-hormonal mechanisms (including glucocorticoids and adrenergic signaling) are activated to orchestrate muscle metabolism. SLN expression is also upregulated under these high-energy demand conditions. Higher SLN/SERCA level leads to higher cytosolic Ca²⁺ and facilitates its uptake into mitochondria, which serves as a trigger for oxidative metabolism. In addition Ca²⁺ -signaling pathways activate increased transcription of genes involved in oxidative metabolism. DHPR- dihydropyridine receptor, GR- glucocorticoid receptor, RYR1- ryanodine receptor 1, SERCA-sarcoplasmic/endoplasmic reticulum calcium ATPase, SLN- sarcolipin, SR- sarcoplasmic reticulum.