Sarcolipin Deletion Exaggerates Muscle Atrophy and Weakness Induced by Phospholamban Overexpression

Sarcolipin (SLN) and phospholamban (PLN) are two small proteins capable of inhibiting the sarco(endo)plasmic reticulum Ca 2+ ‐ATPase (SERCA) pump. Recent work from our laboratory demonstrates that mice overexpressing PLN ( Pln OE / Sln WT ) in their slow‐twitch type I fibers present with severe impairments in SERCA function, soleus muscle atrophy and weakness, and a centronuclear myopathy (CNM)‐like phenotype. Interestingly, SLN protein was also upregulated 9‐fold in the soleus muscles from these mice, which is consistent with other models of muscle disease where SLN is often upregulated. However, to date, the physiological role of upregulated SLN in states of muscle disease remains unknown. Thus, in this study we generated the Pln OE / Sln KO mouse to determine the effects of genetic Sln deletion on SERCA function, muscle structure and contractility. Since, SLN is a potent inhibitor of the SERCA pump, we initially hypothesized that targeting Sln would lead to improvements in SERCA function, muscle contractility, and alleviate the soleus muscle atrophy and CNM‐like phenotype in this model. Surprisingly, we found that rates of Ca 2+ uptake (−18–20%, P ≤ 0.05) and SERCA's apparent affinity for Ca 2+ (Δ K Ca : −0.07 to −0.10 p Ca units, P ≤ 0.05) were similarly reduced in Pln OE / Sln WT and Pln OE / Sln KO mice compared with Pln WT / Sln WT . Consistent with the lack of improvement in SERCA function, the three typical hallmarks of CNM (1. central nuclei, 2. type I fiber predominance and hypotrophy, and 3. central aggregation of oxidative activity) were found in the soleus muscles from both Pln OE / Sln WT and Pln OE / Sln KO mice. Interestingly, Pln OE / Sln KO mice displayed an exaggerated soleus muscle atrophy and weakness indicated through greater reductions in soleus:body weight ratios ( Pln WT / Sln WT , 0.31 ± 0.01, n = 23; Pln OE / Sln WT , 0.25 ± 0.01, n = 22; Pln OE / Sln KO , 0.20 ± 0.01, n =18, P ≤ 0.05, one‐way ANOVA) and a significant reduction in both submaximal and maximal force (50–100 Hz, P ≤ 0.05). Importantly, the greater reductions in muscle size and force production could not be explained by differences in body weight, food intake, or daily activity. Instead, we attributed these effects to the fact that, in the absence of Sln , type II fibers failed to undergo the necessary myofiber hypertrophy and remodeling that compensates for the deleterious effects imposed by PLN overexpression. Furthermore, this failure to promote myofiber hypertrophy and remodeling was associated with a significantly higher level of phophosphorylated nuclear factor of activated T cell ( Pln OE / Sln WT vs. Pln OE / Sln KO −22% phosphorylation, P ≤ 0.05), a well‐known calcineurin substrate. Therefore, these results suggest that SLN counters the muscle atrophy and weakness found in Pln OE mice by stimulating calcinuerin activation. Support or Funding Information This work was supported by the Canadian Institutes of Health Research (CIHR; MOP 86618 and MOP 47296 to A.R.T).

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