Sarcolipin and uncoupling protein 1 play distinct roles in diet‐induced thermogenesis and do not compensate for one another

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

doi:10.1002/oby.21542

Cited by 51 publications

(57 citation statements)

References 19 publications

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“…Increased muscle thermogenesis through the sarcolipin-driven uncoupling of SERCA would increase organismal energy expenditure, thereby resulting in lower adiposity gains. Indeed, this hypothesis is consistent with reports that obesity is exacerbated when Sln is ablated [58][59][60] or prevented when it is Sln is overexpressed [61].…”

Section: Discussionsupporting

confidence: 92%

“…To identify the molecular mechanisms causing increased energy expenditure in muscle Tsc1 knockout mice, we determined the expression of transcripts known to be important contributors to skeletal muscle thermogenesis. We observed dramatic increases in the ATP-dependent SR/ER Ca2+ pump SERCA2 (encoded by Atp2a2, see Figure 4C), and its un-coupler Sarcolipin (encoded by Sln; Figure 4C), proteins previously reported as playing an integral role in muscle-specific thermogenesis [58][59][60][61].…”

Section: Muscle Mtorc1 Activation Increases Thermogenic Signaling Viamentioning

confidence: 69%

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Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

Stephenson

Redd

Snyder

et al. 2019

Preprint

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The mechanistic target of rapamycin (mTORC1) is a nutrient responsive protein kinase complex that helps co-ordinate anabolic processes across all tissues. There is evidence that signaling through mTORC1 in skeletal muscle may be a determinant of energy expenditure and aging and therefore components downstream of mTORC1 signaling may be potential targets for treating obesity and ageassociated metabolic disease. Here, we generated mice with Ckmm-Cre driven ablation of Tsc1, which confers constitutive activation of mTORC1 in skeletal muscle and performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. Activation of skeletal muscle mTORC1 produced a striking resistance to diet-and age-induced obesity without inducing systemic insulin resistance. We found that increases in energy expenditure following a high fat diet were mTORC1-dependent and that elevated energy expenditure caused by ablation of Tsc1 coincided with the upregulation of skeletal musclespecific thermogenic mechanisms that involve sarcolipin-driven futile cycling of Ca 2+ through SERCA2.Additionally, we report that constitutive activation of mTORC1 in skeletal muscle reduces lifespan.These findings support the hypothesis that activation of mTORC1 and its downstream targets, specifically in skeletal muscle, may play a role in nutrient-dependent thermogenesis and aging.Skeletal muscle is the major site of postprandial glucose disposal and the primary determinant of resting energy expenditure in mammals [18,19]. Constitutive activation of mTORC1, via musclespecific deletion of its negative regulator Tsc1, results in age-related myoatrophy, dysregulation of autophagy induction and increased expression of mitochondrial enzymes [6,20,21]. Consistent with the latter, cell culture models implicate mTORC1 as a positive regulator of mitochondrial biogenesis and aerobic ATP production [22][23][24]. During the aging process, skeletal muscle exhibits a fiber-type transformation towards a more oxidative phenotype, concomitant with increased mTORC1 activity. In line with these observations, several studies have implicated mTORC1 inhibition as a mechanism of organismal lifespan extension in yeast, worms and mammals [25][26][27]; however, the tissue or tissues that link mTORC1 activity to lifespan have not yet been identified.Skeletal muscle is an important tissue for understanding aging, insulin sensitivity and changes in energy metabolism, as functional differences in muscle strength predict lifespan in humans [28][29][30][31][32][33].Furthermore, mTORC1 regulates several important metabolic processes in muscle; including oxidative stress, the unfolded protein response, autophagy and lipid metabolism [20,34,35]. Here, we have performed unbiased transcriptional analyses to identify pathways and candidate genes that may explain how skeletal muscle mTORC1 activity regulates energy balance and aging. We show that chronic mTORC1 activation in skeletal muscle (...

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Section: Discussionsupporting

confidence: 92%

Section: Muscle Mtorc1 Activation Increases Thermogenic Signaling Viamentioning

confidence: 69%

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

Stephenson

Redd

Snyder

et al. 2019

Preprint

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“…Therefore, obesity in β-less mice has been directly linked to inhibition of diet-induced thermogenesis, potentially through defective function of target tissues of the sympathetic nervous system. Such possibilities include brown, beige, and white adipose tissues, or skeletal muscle, where diet-induced thermogenesis may be induced by alternative futile cycles (Anunciado-Koza et al, 2008; Granneman et al, 2003; Meyer et al, 2010; Mottillo et al, 2014; Rowland et al, 2016; Ukropec et al, 2006). …”

Section: Introductionmentioning

confidence: 99%

Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity

et al. 2017

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SUMMARY Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue has not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high calorie feeding. This is paralleled by a blunted capacity for β3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong in vivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity.

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“…Millipore-Sigma reports that ABT13 reacts with rabbit, mouse, and human SLN on immunoblot at 1.5 µg/mL pAb, as corroborated for rabbit SLN using 0.5 µg/mL pAb ABT13 (1:1000 dilution) and fluorescent secondary antibody detection (Figure S8). pAb ABT13 has been validated for SLN immunoblotting using human right atrium homogenate (189) and mouse soleus and diaphragm homogenates (190). Here pAb ABT13 was used for primary labeling at 1:1000 dilution, with positive detection of SLN in rabbit SR (Figure S7), plus synthetic rabbit and human SLN.…”

Section: Commercial Anti-sln Polyclonal Antibodiesmentioning

confidence: 99%

Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport

Karim

Svensson

et al. 2019

Preprint

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We have analyzed gene transcription, protein expression, and enzymatic activity of the Ca 2+ -transporting ATPase (SERCA) in horse gluteal muscle. Horses are bred for peak athletic performance but exhibit a high incidence of exertional rhabdomyolysis, with myosolic Ca 2+ suggested as a correlative linkage. To assess Ca 2+ regulation in horse gluteus, we developed an improved protocol for isolating horse sarcoplasmic reticulum (SR) vesicles. RNA-seq and immunoblotting determined that the ATP2A1 gene (protein product SERCA1) is the predominant Ca 2+ -ATPase expressed in horse gluteus, as in rabbit muscle. Gene expression was assessed for four regulatory peptides of SERCA, finding that sarcolipin (SLN) is the predominant regulatory peptide transcript expressed in horse gluteus, as in rabbit muscle. Surprisingly, the RNA transcription ratio of SLN-to-ATP2A1 in horse gluteus is an order of magnitude higher than in rabbit muscle, but conversely, the protein expression ratio of SLN-to-SERCA1 in horse gluteus is an order of magnitude lower than in rabbit. Thus, the SLN gene is not translated to a stable protein in horse gluteus, yet the suprahigh level of SLN RNA suggests a non-coding role. Gel-stain analysis revealed that horse SR expresses calsequestrin (CASQ) protein abundantly, with a CASQ-to-SERCA ratio ~3-fold greater than rabbit SR. The Ca 2+ transport rate of horse SR vesicles is ~2-fold greater than rabbit SR, suggesting horse myocytes have enhanced luminal Ca 2+ stores that increase intracellular Ca 2+ release and muscular performance. The absence of SLN inhibition of SERCA and the abundant expression of CASQ may potentiate horse muscle contractility and susceptibility to exertional rhabdomyolysis. The horse has been selectively bred for thousands of years to achieve remarkable athletic ability, in part conferred by a naturally-high proportion (75-95%) of fast-twitch myofibers in locomotor muscles that provide powerful contractions and high speed (1). Calcium (Ca 2+ ) 1 is the signaling molecule that controls muscle contraction by activating the actomyosin sliding-filament mechanism (2). In turn, myosolic Ca 2+ is controlled predominantly by the sarcoplasmic reticulum (SR), a membrane organelle that connects with transverse tubules as membrane junctions and also surrounds actomyosin myofibrils as longitudinal sheaths (3). Thus, SR is a dual structure/function membrane system comprising junctional SR with the ryanodine receptor Ca 2+ release channel (RYR) acting to initiate contraction, and longitudinal SR with the Ca 2+ transporting ATPase (SERCA) acting to induce relaxation (4,5). For muscle contraction, the bolus of released Ca 2+ originates almost solely from SR through the RYR channel, and this released Ca 2+ is subsequently re-sequestered in the SR lumen by SERCA (6). The strength of muscle contraction is controlled by the amount of Ca 2+ released from SR, which is in turn modulated by the Ca 2+ load in the SR lumen (7). Calsequestrin (CASQ), which binds up to 80 Ca 2+ ions (mol/mol), is the high-capacity ...

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Sarcolipin and uncoupling protein 1 play distinct roles in diet‐induced thermogenesis and do not compensate for one another

Cited by 51 publications

References 19 publications

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

Skeletal Muscle mTORC1 Activation Increases Energy Expenditure and Reduces Longevity in Mice

Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity

Horse gluteus is a null-sarcolipin muscle with enhanced sarcoplasmic reticulum calcium transport

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