title: Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals.
abstract: The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca(2+), which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism.
authors.affiliation: Department of Physiology and Cell Biology, Ohio State University, College of Medicine, Columbus, Ohio, USA.
authors.forename: Naresh C
authors.initials: NC
authors.lastname: Bal
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Maurya
authors.forename: Danesh H
authors.initials: DH
authors.lastname: Sopariwala
authors.forename: Sanjaya K
authors.initials: SK
authors.lastname: Sahoo
authors.forename: Subash C
authors.initials: SC
authors.lastname: Gupta
authors.forename: Sana A
authors.initials: SA
authors.lastname: Shaikh
authors.forename: Meghna
authors.initials: M
authors.lastname: Pant
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Rowland
authors.forename: Eric
authors.initials: E
authors.lastname: Bombardier
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.forename: A Russell
authors.initials: AR
authors.lastname: Tupling
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001833:Body Temperature Regulation / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004734:Energy Metabolism / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D011510:Proteolipids / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D022722:Thermogenesis / Q000502:physiology*; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D011510:Proteolipids; D019837:Ryanodine Receptor Calcium Release Channel; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C077258:sarcolipin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium