Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

Voit, Antanina; Patel, Vikas; Pachon, Ronald; Shah, Vikas; Bakhutma, Mohammad; Kohlbrenner, Erik; McArdle, Joseph J.; Dell’Italia, Louis J.; Mendell, Jerry R.; Xie, Lai-Hua; Hajjar, Roger J.; Duan, Dongsheng; Fraidenraich, Diego; Babu, Gopal J.

doi:10.1038/s41467-017-01146-7

Cited by 95 publications

(143 citation statements)

References 71 publications

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“…However, studies using strength training programs or analyzing the effects of immobilization are required to confirm this finding. Finally, it is unclear whether an increase of SLN expression could be an effective treatment to counteract obesity in humans without causing muscular dystrophy …”

Section: Discussionmentioning

confidence: 99%

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Morales-Álamo

Martinez‐Canton²,

Gelabert‐Rebato

et al. 2019

Scandinavian Med Sci Sports

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Sarcolipin (SLN) is a SERCA uncoupling protein associated with exercise performance and lower adiposity in mice. To determine SLN protein expression in human skeletal muscle and its relationship with adiposity, resting energy expenditure (REE), and performance, SLN was assessed by Western blot in 199 biopsies from two previous studies. In one study, 15 overweight volunteers underwent a pretest followed by 4 days of caloric restriction and exercise (45‐minute one‐arm cranking + 8‐hour walking), and 3 days on a control diet. Muscle biopsies were obtained from the trained and non‐exercised deltoid, and vastus lateralis (VL). In another study, 16 men performed seven sessions of 4‐6 × 30‐sec all‐out sprints on the cycle ergometer with both limbs, and their VL and triceps brachii biopsied pre‐ and post‐training. SLN expression was twofold and 44% higher in the VL than in the deltoids and triceps brachii, respectively. SLN was associated with neither adiposity nor REE, and was not altered by a severe energy deficit (5500 kcal/day). SLN and cortisol changes after the energy deficit were correlated (r = .38, P = .039). SLN was not altered by low‐intensity exercise in the overweight subjects, whereas it was reduced after sprint training in the other group. The changes in SLN with sprint training were inversely associated with the changes in gross efficiency (r = −.59, P = .016). No association was observed between aerobic or anaerobic performance and SLN expression. In conclusion, sarcolipin appears to play no role in regulating the fat mass of men. Sprint training reduces sarcolipin expression, which may improve muscle efficiency.

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Section: Discussionmentioning

confidence: 99%

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Morales-Álamo

Martinez‐Canton²,

Gelabert‐Rebato

et al. 2019

Scandinavian Med Sci Sports

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“…In human muscular dystrophies, the effect of modulating SLN expression level and inhibitory function is unknown. In compelling mouse and canine models, enhancing SLN protein expression has been proposed as an effective therapy, as reported by Babu et al (155). Indeed, SLN gene expression and protein levels are increased many-fold in standard mouse models of Duchenne's muscular dystrophy, e.g., mdx and mdx/utr-dko (36).…”

Section: Proposed Role Of Sln Expression In Horse Exertional Rhabdomymentioning

confidence: 98%

“…Indeed, SLN gene expression and protein levels are increased many-fold in standard mouse models of Duchenne's muscular dystrophy, e.g., mdx and mdx/utr-dko (36). However, decreasing SLN expression in mouse models is reported to have beneficial or deleterious effects, depending on the genetic model and etiology studied (155)(156)(157). To help delineate these disparate effects, additional correlations should be determined among Ca 2+ transport regulation and muscular performance in animal models and human disease, which may then provide insights on utilization of species-dependent mechanisms for contractile and therapeutic control.…”

Section: Proposed Role Of Sln Expression In Horse Exertional Rhabdomymentioning

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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“…By contrast, SLN was found to be down‐regulated in patients with chronic atrial fibrillation . In Duchenne muscular dystrophy mice, a reduction in SLN expression was found to mitigate associated cardiomyopathy …”

Section: Introductionmentioning

confidence: 97%

“…19 In Duchenne muscular dystrophy mice, a reduction in SLN expression was found to mitigate associated cardiomyopathy. 20 Alone, the SLN promoter activity is unsubstantial compared to that of ubiquitous promoters. Thus, the addition of calsequestrin 2 cis-regulatory module 4 (CRM4), a cardiomyocyte-specific enhancer, which showed superior activity in the heart, was used to heighten transgene expression of SLN within the heart.…”

mentioning

confidence: 99%

Enhancing atrial‐specific gene expression using a calsequestrin cis‐regulatory module 4 with a sarcolipin promoter

Yoo

Kohlbrenner

Kim

et al. 2018

The Journal of Gene Medicine

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Background Cardiac gene therapy using the adeno‐associated virus serotype 9 vector is widely used because of its efficient transduction. However, the promoters used to drive expression often cause off‐target localization. To overcome this, studies have applied cardiac‐specific promoters, although expression is debilitated compared to that of ubiquitous promoters. To address these issues in the context of atrial‐specific gene expression, an enhancer calsequestrin cis‐ regulatory module 4 ( CRM4 ) and the highly atrial‐specific promoter sarcolipin were combined to enhance expression and minimize off tissue expression. Methods To observe expression and bio‐distribution, constructs were generated using two different reporter genes: luciferase and enhanced green fluorescent protein (EGFP). The ubiquitous cytomegalovirus (CMV), sarcolipin (SLN) and CRM4 combined with sarcolipin ( CRM4 .SLN) were compared and analyzed using the luciferase assay, western blotting, a quantitative polymerase chain reaction and fluorescence imaging. Results The CMV promoter containing vectors showed the strongest expression in vitro and in vivo . However, the module SLN combination showed enhanced atrial expression and a minimized off‐target effect even when compared with the individual SLN promoter. Conclusions For gene therapy involving atrial gene transfer, the CRM4 .SLN combination is a promising alternative to the use of the CMV promoter. CRM4 .SLN had significant atrial expression and minimized extra‐atrial expression.

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Reducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice

Cited by 95 publications

References 71 publications

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

Sarcolipin expression in human skeletal muscle: Influence of energy balance and exercise

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

Enhancing atrial‐specific gene expression using a calsequestrin cis‐regulatory module 4 with a sarcolipin promoter

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