Phospholamban overexpression in mice causes a centronuclear myopathy-like phenotype

Fajardo, Val A.; Bombardier, Éric; McMillan, Elliott M.; Tran, Khanh; Wadsworth, Brennan J.; Gamu, Daniel; Hopf, Andrew; Vigna, Chris; Smith, Ian D.; Bellissimo, Catherine A.; Michel, Robin N.; Tarnopolsky, Mark A.; Quadrilatero, Joe; Tupling, A. Russell

doi:10.1242/dmm.020859

Cited by 30 publications

(62 citation statements)

References 70 publications

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“…Furthermore, the type IIA fibers from Pln OE / Sln KO mice failed to undergo the typical compensatory hypertrophy observed in the Pln OE mice (Fig 3F and reference [3]), and the type IIX fibers showed a similar pattern (Fig 3F); however the one-way ANOVA did not indicate statistical significance ( p = 0.11). There was also a significant reduction in total fiber count in the Pln OE / Sln KO soleus muscles compared with both Pln OE and WT mice (Fig 4B).…”

Section: Resultsmentioning

confidence: 87%

Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice

et al. 2017

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Sarcolipin (SLN) and phospholamban (PLN) are two small proteins that regulate the sarco(endo)plasmic reticulum Ca2+-ATPase pumps. In a recent study, we discovered that Pln overexpression (PlnOE) in slow-twitch type I skeletal muscle fibers drastically impaired SERCA function and caused a centronuclear myopathy-like phenotype, severe muscle atrophy and weakness, and an 8 to 9-fold upregulation of SLN protein in the soleus muscles. Here, we sought to determine the physiological role of SLN upregulation, and based on its role as a SERCA inhibitor, we hypothesized that it would represent a maladaptive response that contributes to the SERCA dysfunction and the overall myopathy observed in the PlnOE mice. To this end, we crossed Sln-null (SlnKO) mice with PlnOE mice to generate a PlnOE/SlnKO mouse colony and assessed SERCA function, CNM pathology, in vitro contractility, muscle mass, calcineurin signaling, daily activity and food intake, and proteolytic enzyme activity. Our results indicate that genetic deletion of Sln did not improve SERCA function nor rescue the CNM phenotype, but did result in exacerbated muscle atrophy and weakness, due to a failure to induce type II fiber compensatory hypertrophy and a reduction in total myofiber count. Mechanistically, our findings suggest that impaired calcineurin activation and resultant decreased expression of stabilin-2, and/or impaired autophagic signaling could be involved. Future studies should examine these possibilities. In conclusion, our study demonstrates the importance of SLN upregulation in combating muscle myopathy in the PlnOE mice, and since SLN is upregulated across several myopathies, our findings may reveal SLN as a novel and universal therapeutic target.

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Section: Resultsmentioning

confidence: 87%

Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice

et al. 2017

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“…We have recently reported that the Pln OE mouse histopathologically resembles human autosomal dominant CNM (Fajardo et al. ), which, in contrast to myotubular myopathy, is generally less severe, and patients often have a normal lifespan with very few respiratory complications (Bitoun et al. ; Jungbluth et al.…”

Section: Discussionmentioning

confidence: 99%

“…Western blot analysis was performed to determine expression levels of SERCAs, SLN, PLN, and dynamin 2 in the diaphragm muscles from WT and Pln OE mice as previously described (Fajardo et al. ). In addition, calcineurin expression and NFAT nuclear localization in soleus, gluteus minimus, and diaphragm muscles were assessed.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we found that the soleus and gluteus minimus muscles from mice overexpressing PLN ( Pln OE ) in their slow‐twitch type I skeletal muscle fibers had impaired SERCA function and displayed the histopathological features associated with human CNM (Fajardo et al. ). Based on the appearance of radiating sarcoplasmic strands, type II fiber hypertrophy, and endomysial fibrosis, the CNM observed in the Pln OE mice resembles human autosomal dominant CNM and, to an extent, RYR ‐related and TTN ‐related CNM (Jungbluth and Gautel ).…”

Section: Introductionmentioning

confidence: 99%

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Diaphragm assessment in mice overexpressing phospholamban in slow‐twitch type I muscle fibers

et al. 2016

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AimsPhospholamban (PLN) and sarcolipin (SLN) are small inhibitory proteins that regulate the sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) pump. Previous work from our laboratory revealed that in the soleus and gluteus minimus muscles of mice overexpressing PLN (Pln OE), SERCA function was impaired, dynamin 2 (3–5 fold) and SLN (7–9 fold) were upregulated, and features of human centronuclear myopathy (CNM) were observed. Here, we performed structural and functional experiments to evaluate whether the diaphragm muscles of the Pln OE mouse would exhibit CNM pathology and muscle weakness.MethodsDiaphragm muscles from Pln OE and WT mice were subjected to histological/histochemical/immunofluorescent staining, Ca2+‐ATPase and Ca2+ uptake assays, Western blotting, and in vitro electrical stimulation.ResultsOur results demonstrate that PLN overexpression reduced SERCA's apparent affinity for Ca2+ but did not reduce maximal SERCA activity or rates of Ca2+ uptake. SLN was upregulated 2.5‐fold, whereas no changes in dynamin 2 expression were found. With respect to CNM, we did not observe type I fiber predominance, central nuclei, or central aggregation of oxidative activity in diaphragm, although type I fiber hypotrophy was present. Furthermore, in vitro contractility assessment of Pln OE diaphragm strips revealed no reductions in force‐generating capacity, maximal rates of relaxation or force development, but did indicate that ½ relaxation time was prolonged.ConclusionsTherefore, the effects of PLN overexpression on skeletal muscle phenotype differ between diaphragm and the postural soleus and gluteus minimus muscles. Our findings here point to differences in SLN expression and type I fiber distribution as potential contributing factors.

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“…SLN expression is also developmentally regulated in rodents; it is relatively high in fetal and neonatal skeletal muscles but gradually becomes restricted to slow-twitch oxidative muscle fibers in adult rodents [34]. The expression of SLN is independently regulated from SERCA and can be affected by disease states [35, 36]. The expression of SLN varies in small and large mammals.…”

Section: Sarcoplasmic Reticulum Is a Critical Player In Muscle Physiomentioning

confidence: 99%

Sarcolipin is a novel regulator of muscle metabolism and obesity

Maurya

Periasamy

2015

Pharmacological Research

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Obesity is increasing at an alarming rate, both in adults and adolescents, across the globe due to increased consumption of caloric rich diet. Obesity and its associated complications appear to be major contributing factors not only to diabetes/heart disease but also to cancer, and neurological diseases causing a huge burden on the health care system. To date, there are no effective treatments to reduce weight gain, other than caloric restriction and exercise which are often difficult to enforce. There are very few drugs available for treating obesity and those that are available only reduce obesity by ~10%. Identifying mechanisms to increase energy expenditure, on top of the increase elicited by exercise, would be more beneficial to control weight gain. The purpose of this review is to highlight the role of sarcolipin (SLN), a regulator of SERCA pump, in muscle thermogenesis and metabolism. We will further discuss if enhancing SLN activity could be an effective mechanism to increase energy expenditure and control weight gain. We will also discuss the merits of adaptive thermogenesis in muscle and brown fat as potential mechanisms to increase energy expenditure during caloric overload. That said, there is still a great need for further research into the mechanism of diet induced thermogenesis and its relevance to overall metabolism and obesity.

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Phospholamban overexpression in mice causes a centronuclear myopathy-like phenotype

Cited by 30 publications

References 70 publications

Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice

Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice

Diaphragm assessment in mice overexpressing phospholamban in slow‐twitch type I muscle fibers

Sarcolipin is a novel regulator of muscle metabolism and obesity

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