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

Abstract

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.

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

“…Altered expression of SLN at the mRNA and protein levels have been reported in the diseased myocardium of human 39 – 42 and in animal models 33 , 43 , 44 , as well as in mouse models with skeletal muscle pathology 45 – 48 . However, the functional consequences of altered SLN expression in cardiac and skeletal muscle pathology are not fully understood.…”

“…However, the functional consequences of altered SLN expression in cardiac and skeletal muscle pathology are not fully understood. A recent study shows that complete loss of SLN fails to improve SERCA function and a centronuclear myopathy-like phenotype in transgenic mice with skeletal muscle specific PLN overexpression 45 . On the other hand, SLN ablation results in exacerbated muscle atrophy and weakness with impaired calcineurin pathway, suggesting that SLN overexpression may have compensatory effects on muscle function in these mice 45 .…”

Calmodulin-Binding Proteins in Muscle: A Minireview on Nuclear Receptor Interacting Protein, Neurogranin, and Growth-Associated Protein 43

“…Collectively, these studies demonstrate the importance of CaN and CaMKII in mitigating a dystrophic pathology. Indeed, there are other muscle diseases in which activating these CaM-dependent proteins could lead to physiological benefits, including myotonic dystrophy type 1 [65] and centronuclear myopathy [66]. Therefore, the regulation of CaM availability will have a significant physiological impact on a number of muscle myopathies.…”

Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis

“…Researchers have observed increased Sln expression levels in various forms of muscular dystrophy (Bal et al, 2012;Fajardo et al, 2018Fajardo et al, , 2017Pant, Bal, & Periasamy, 2016). To characterize the physiological role of Sln upregulation in Lmna −/− mice, we created Sln knockout (Sln −/− ) mice ( Figure 1c) using the CRISPR/Cas9-mediated genome engineering technique (Zhou et al, 2014).…”