The effects of sarcolipin over-expression in mouse skeletal muscle on metabolic activity

Butler, J. A. V.; Smyth, Neil; Broadbridge, Robert J.; Lee, Anthony G.; Stocker, Claire J.; Hislop, David C.; Arch, Jonathan R.S.; Cawthorne, Michael A.; East, J. Malcolm

doi:10.1016/j.abb.2015.01.027

Cited by 13 publications

(17 citation statements)

References 18 publications

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“…Although SLN is only expressed in amounts likely to small to have a measurable effect on thermogenesis in mice with intact BAT/UCP1 (Butler et al, 2015 ), SLN has been proven to be important for maintenance of endothermy when NST in BAT is not possible (Bal et al, 2012 ). Interestingly, both mechanisms of NST—UCP1-mediated as well as muscle NST—can compensate for the loss of one system, while double-knockout mice without UCP1 and SLN are unable to survive during prolonged cold exposure, indicating that at least one of the two mechanisms is pivotal to maintain endothermy (Rowland et al, 2015 ).…”

Section: Importance Of Muscle Nst In Mammalsmentioning

confidence: 99%

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

et al. 2017

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The development of sustained, long-term endothermy was one of the major transitions in the evolution of vertebrates. Thermogenesis in endotherms does not only occur via shivering or activity, but also via non-shivering thermogenesis (NST). Mammalian NST is mediated by the uncoupling protein 1 in the brown adipose tissue (BAT) and possibly involves an additional mechanism of NST in skeletal muscle. This alternative mechanism is based on Ca 2+ -slippage by a sarcoplasmatic reticulum Ca 2+ -ATPase (SERCA) and is controlled by the protein sarcolipin. The existence of muscle based NST has been discussed for a long time and is likely present in all mammals. However, its importance for thermoregulation was demonstrated only recently in mice. Interestingly, birds, which have evolved from a different reptilian lineage than mammals and lack UCP1-mediated NST, also exhibit muscle based NST under the involvement of SERCA, though likely without the participation of sarcolipin. In this review we summarize the current knowledge on muscle NST and discuss the efficiency of muscle NST and BAT in the context of the hypothesis that muscle NST could have been the earliest mechanism of heat generation during cold exposure in vertebrates that ultimately enabled the evolution of endothermy. We suggest that the evolution of BAT in addition to muscle NST was related to heterothermy being predominant among early endothermic mammals. Furthermore, we argue that, in contrast to small mammals, muscle NST is sufficient to maintain high body temperature in birds, which have enhanced capacities to fuel muscle NST by high rates of fatty acid import.

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Section: Importance Of Muscle Nst In Mammalsmentioning

confidence: 99%

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

et al. 2017

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“…On immunoblots, the small amount of horse SLN in native SR vesicles migrates as a monomer on SDS-PAGE (Figure 5C, Figure S6), as is typically found for rabbit SLN in SR vesicles, and also other orthologs (mouse, dog, and pig) in respective SR vesicles (26, 28,78,102). On the other hand, purified SLN (native, recombinant, or synthetic) on SDS-PAGES migrates often as a mix of oligomeric species: abundantlypopulated monomers with a variable amount of dimers, and sometimes with lowly-populated trimers and/or tetramers (29,31,(105)(106)(107) (Figure 5, Figure S9).…”

Section: Horse Gluteal Muscle Expresses a Minor Level Of Sln Protein mentioning

confidence: 56%

“…Our custom antibody GS3379 successfully detected synthetic horse SLN, yet found minimal level of SLN expressed in horse SR. By correlating the gene expression of SLN with the protein expression of SLN, we find that the high level of SLN RNA transcripts does not produce significant SLN protein. For comparison, rabbit skeletal muscle is reported to express 0.75 or 1.2 SLN per SERCA (mol/mol) (29,102). Thus, we suggest that horse gluteus is the first demonstration of a native skeletal muscle that shows insignificant-to-undetectable expression of known regulatory peptides of SERCA in muscle.…”

Section: Positive and Negative Correlations Of Gene Transcription Andmentioning

confidence: 75%

“…When correlating the gene expression of SLN versus the protein expression of SLN in horse muscle (normalized per ATP2A1 or SERCA1, respectively), we find that the high level of SLN RNA, with SLN/total-ATP2A = 9.1 ± 3.7 (TPM/TPM) ( Figure 1C), produces only an insignificant amount of SLN regulatory peptide, with a protein expression ration of SLN/SERCA = 0.059 ± 0.005 (mol/mol) (Figure 5, Figures S4-S6). On the other hand, rabbit skeletal muscle produces a relative gene expression ratio of SLN/total-ATP2A = 3.0 ± 0.2 (TPM/TPM) ( Figure 1C) and a protein expression ratio of 0.75-1.2 SLN/SERCA (mol/mol) (29,102). Thus, horse muscle lacks correlation of gene and protein expression levels for SLN and SERCA, unlike rabbit muscle.…”

Section: Horse Gluteal Muscle Expresses a Minor Level Of Sln Protein mentioning

confidence: 98%

“…We utilized quantitative immunoblotting and Coomassie densitometry to compare the relative amount of SERCA protein in SR vesicles from horse versus rabbit muscle. For standardization, the SERCA content of SR vesicles from rabbit fast-twitch (white) muscle has been determined to be 55-70% of total protein (weight/weight), i.e., 5.0-6.4 nmol SERCA/mg rabbit SR protein (98,(100)(101)(102). Immunoblotting with anti-SERCA1 mAb VE12 1 G9 demonstrated that SR vesicles from horse gluteal muscle express ~35% the relative amount of SERCA1 as compared to rabbit SR (Figure 5A, Figure S5), although this is probably a slight underestimate of total SERCA content, since horse SR (10KP) also expresses a small amount of ATP2A2 (SERCA2) (Figure 1), which is incompatible with the use of anti-SERCA1 mAb VE12 1 G9.…”

Section: An Improved Fractionation Protocol Increases the Purity Of Smentioning

confidence: 99%

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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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Functional and Structural Insights into Sarcolipin, a Regulator of the Sarco-Endoplasmic Reticulum Ca2+-ATPases

Barbot¹,

Montigny²,

Decottignies³

et al. 2015

Regulation of Ca2+-ATPases,V-ATPases and F-ATPases

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The effects of sarcolipin over-expression in mouse skeletal muscle on metabolic activity

Cited by 13 publications

References 18 publications

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy

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

Functional and Structural Insights into Sarcolipin, a Regulator of the Sarco-Endoplasmic Reticulum Ca2+-ATPases

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