Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress

Rowland, Leslie A.; Bal, Naresh C.; Kozak, Leslie P.; Periasamy, Muthu

doi:10.1074/jbc.m115.637603

Cited by 102 publications

(126 citation statements)

References 46 publications

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“…Moreover, the ability to recruit SLN/SERCA-mediated muscle-based NST without significantly affecting muscle maturation and function will be favorably selected for, specifically in non-tropical climates where temperature and food availability dramatically fluctuate seasonally. Recent studies from our lab further show that SLN increases fatigue resistance of muscle while increasing energy expenditure and contributes to thermogenesis (Maurya et al, 2015;Rowland et al, 2015;Sopariwala et al, 2015). Collectively, these findings along with our data suggest that SLN is an important marker of muscle-based thermogenesis.…”

Section: Resultssupporting

confidence: 65%

“…In mice, brown adipose tissue (BAT) has been implicated as a major contributor to NST (Cannon and Nedergaard, 2004). However, recent studies by others and by us have shown that apart from shivering, skeletal muscle is also an important site of NST (Bal et al, 2012;Rowland et al, 2015;McKay et al, 2013;Louzada et al, 2014). We have demonstrated that skeletal muscle-based NST is largely mediated by a sarcoplasmic reticulum (SR) membrane protein called sarcolipin (SLN) (Bal et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

Pant

Bal

Periasamy

2015

Journal of Experimental Biology

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Neonatal mice have a greater thermogenic need than adult mice and may require additional means of heat production, other than the established mechanism of brown adipose tissue (BAT). We and others recently discovered a novel mediator of skeletal muscle-based thermogenesis called sarcolipin (SLN) that acts by uncoupling sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA). In addition, we have shown that SLN expression is downregulated during neonatal development in rats. In this study we probed two questions: (1) is SLN expression developmentally regulated in neonatal mice?; and (2) if so, will cold adaptation override this? Our data show that SLN expression is higher during early neonatal stages and is gradually downregulated in fast twitch skeletal muscles. Interestingly, we demonstrate that cold acclimation of neonatal mice can prevent downregulation of SLN expression. This observation suggests that SLN-mediated thermogenesis can be recruited to a greater extent during extreme physiological need, in addition to BAT.

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Section: Resultssupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

Pant

Bal

Periasamy

2015

Journal of Experimental Biology

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“…We have shown that mice lacking SLN were cold-sensitive, indicating a role of SLN in muscle-based NST (13). In addition, we showed that cold acclimatization of UCP 1 knockout mice (UCP 1-KO) up-regulated SLN expression in skeletal muscles, suggesting that muscle thermogenesis is recruited to a greater extent when BAT function is lost (14). Furthermore, cold adaptation studies using neonatal mice firmly suggest that muscle serves as a site of thermogenesis beyond shivering (23).…”

mentioning

confidence: 73%

“…20,21). Recently, we reported that modulation of SER Ca 2ϩ cycling by sarcolipin (SLN) in skeletal muscle plays an important role in NST (13,14,(22)(23)(24). Our data indicated that binding of SLN to sarcoendoplasmic reticulum Ca 2ϩ ATPase (SERCA) uncouples ATP hydrolysis from its Ca 2ϩ uptake function, leading to futile Ca 2ϩ cycling and heat production (22,25).…”

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confidence: 98%

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Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function

Bal

Maurya

Singh

et al. 2016

Journal of Biological Chemistry

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102

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Skeletal muscle has been suggested as a site of nonshivering thermogenesis (NST) besides brown adipose tissue (BAT). Studies in birds, which do not contain BAT, have demonstrated the importance of skeletal muscle-based NST. However, musclebased NST in mammals remains poorly characterized. We recently reported that sarco/endoplasmic reticulum Ca 2؉ cycling and that its regulation by SLN can be the basis for muscle NST. Because of the dominant role of BAT-mediated thermogenesis in rodents, the role of muscle-based NST is less obvious. In this study, we investigated whether muscle will become an important site of NST when BAT function is conditionally minimized in mice. We surgically removed interscapular BAT (iBAT, which constitutes ϳ70% of total BAT) and exposed the mice to prolonged cold (4°C) for 9 days. The iBAT-ablated mice were able to maintain optimal body temperature (ϳ35-37°C) during the entire period of cold exposure. After 4 days in the cold, both sham controls and iBAT-ablated mice stopped shivering and resumed routine physical activity, indicating that they are cold-adapted. The iBAT-ablated mice showed higher oxygen consumption and decreased body weight and fat mass, suggesting an increased energy cost of cold adaptation. The skeletal muscles in these mice underwent extensive remodeling of both the sarcoplasmic reticulum and mitochondria, including alteration in the expression of key components of Ca 2؉ handling and mitochondrial metabolism. These changes, along with increased sarcolipin expression, provide evidence for the recruitment of NST in skeletal muscle. These studies collectively suggest that skeletal muscle becomes the major site of NST when BAT activity is minimized.

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Role of SERCA Pump in Muscle Thermogenesis and Metabolism

Periasamy

Maurya

Sahoo

et al. 2017

Comprehensive Physiology

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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.

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Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress

Cited by 102 publications

References 46 publications

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

Cold adaptation overrides developmental regulation of sarcolipin expression in mice skeletal muscle: SOS for muscle-based thermogenesis?

Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function

Role of SERCA Pump in Muscle Thermogenesis and Metabolism

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