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The diverse roles of phospholamban and sarcolipin in skeletal muscle: From adaptive thermogenesis to muscle myopathy

A.R. Tupling, Department of Kinesiology, University of Waterloo, 200 University Ave. W., Waterloo, Ontario N2L 3G1, Canada.

Phosopholamban (PLN) and sarcolipin (SLN) are small sarcoplasmic reticulum (SR) proteins that regulate SERCA pump function through physical interactions. My research program aims to advance fundamental understanding of the physiological roles of PLN and SLN in skeletal muscle. In 2008, we began a program of research to investigate the hypothesis that the primary physiological function of SLN in skeletal muscle may be to regulate thermogenesis by SERCA pumps. Overall, we have established that SERCA pumps are important contributors to muscle metabolic rate (Smith et al., 2013) and that SLN, by uncoupling Ca2+ transport from ATP hydrolysis by SERCAs (Bombardier et al., 2013b), is protective against diet-induced obesity, providing a novel mechanism of adaptive thermogenesis within skeletal muscle (Bal et al., 2012; Bombardier et al., 2013a; Gamu et al., 2014). We also published the first study on SLN in human skeletal muscle revealing its co-expression with SERCA isoforms, PLN and myosin heavy chain isoforms in vastus lateralis (Fajardo et al., 2013). Therefore, research in our laboratory has contributed very significantly to the elucidation of the physiological function of SLN in skeletal muscle but the role of PLN in skeletal muscle is not well understood. We are utilizing single and double knock-out models to examine the physiological role of PLN in adaptive thermogenesis. Our preliminary data indicate that the response of PLN to diet overload differs from that of SLN. We have also discovered that PLN overexpression in mouse slow-twitch skeletal muscle (PlnOE) causes centronuclear myopathy (CNM) with core-like lesions and dystrophic features, a phenotype that is associated with significant up-regulation of muscle SLN content, impaired SERCA function and increased Ca2+-activated proteolysis (Fajardo et al., 2015). Interestingly, SLN protein is also up-regulated in other mouse models of myopathy including Duchenne muscular dystrophy (i.e. mdx mice). Therefore, targeting SLN and PLN may represent novel therapeutic approaches to improve SERCA function and oppose skeletal muscle myopathy. We are currently testing these hypotheses using PlnOE/Sln-null and mdx/Sln-null mice and our findings have uncovered a novel physiological role of SLN in skeletal muscle.

Bal NC, Maurya SK, Sopariwala DH, Sahoo SK, Gupta SC, Shaikh SA, Pant M, Rowland LA, Bombardier E, Goonasekera SA, Tupling AR, Molkentin JD, Periasamy M. (2012) Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals. Nat Med 18: 1575-9. doi: 10.1038/nm.2897

Bombardier E, Smith IC, Gamu D, Fajardo VA, Vigna C, Sayer RA, Gupta SC, Bal NC, Periasamy M, Tupling AR. (2013a) Sarcolipin trumps β-adrenergic receptor signaling as the favored mechanism for muscle-based diet-induced thermogenesis. FASEB J 27: 3871-8. doi: 10.1096/fj.13-230631

Bombardier E, Smith IC, Vigna C, Fajardo VA, Tupling AR. (2013b) Ablation of sarcolipin decreases the energy requirements for Ca2+ transport by sarco(endo)plasmic reticulum Ca2+-ATPases in resting skeletal muscle. FEBS Lett 587: 1687-92. doi: 10.1016/j.febslet.2013.04.019

Fajardo VA, Bombardier E, McMillan E, Tran K, Wadsworth BJ, Gamu D, Hopf A, Vigna C, Smith IC, Bellissimo C, Michel RN, Tarnopolsky MA, Quadrilatero J, Tupling AR. (2015) Phospholamban overexpression in mice causes a centronuclear myopathy-like phenotype. Dis Model Mech 8: 999-1009. doi: 10.1242/dmm.020859

Fajardo VA, Bombardier E, Vigna C, Devji T, Bloemberg D, Gamu D, Gramolini AO, Quadrilatero J, Tupling AR. (2013) Co-expression of SERCA isoforms, phospholamban and sarcolipin in human skeletal muscle fibers. PLoS One 8(12): e84304. doi: 10.1371/journal.pone.0084304

Gamu D, Bombardier E, Smith IC, Fajardo VA, Tupling AR. (2014) Sarcolipin provides a novel muscle-based mechanism for adaptive thermogenesis. Exerc Sport Sci Rev 42: 136-42. doi: 10.1249/JES.0000000000000016

Smith IC, Bombardier E, Vigna C, Tupling AR. (2013) ATP consumption by sarcoplasmic reticulum Ca2+ pumps accounts for 40-50% of resting metabolic rate in mouse fast and slow twitch skeletal muscle. PLoS One 8(7): e68924. doi: 10.1371/journal.pone.0068924