Key result
Genetic deletion of sarcolipin in phospholamban overexpressing mice did not improve SERCA function but exacerbated soleus muscle atrophy and weakness by preventing compensatory type II fiber hypertrophy.
Why the study?
Does genetic deletion of Sln improve SERCA function and rescue the CNM phenotype in PlnOE mice?
Does genetic deletion of Sln improve SERCA function and rescue the CNM phenotype in PlnOE mice?
SLN upregulation serves as a compensatory mechanism to combat muscle myopathy in PlnOE mice, suggesting SLN may be a novel therapeutic target for myopathies.
Sarcolipin deletion may worsen muscle outcomes without SERCA benefit; leaves open its therapeutic targeting in phospholamban cardiomyopathy.
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.
No takes yet. Share an insight, caveat, or question.
Fajardo et al. (2017) studied Centronuclear myopathy-like phenotype. Sarcolipin (Sln) genetic deletion vs. Phospholamban overexpressing (PlnOE) mice with intact Sln and wild-type mice was evaluated on Soleus muscle mass and contractile function. Genetic deletion of sarcolipin in phospholamban overexpressing mice did not improve SERCA function but exacerbated soleus muscle atrophy and weakness by preventing compensatory type II fiber hypertrophy.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: