Mechanically Overloaded Plantaris Muscles Display Ectopic Sarcolipin Expression that is Required for Myofiber Hypertrophy and Remodelling

Abstract

Sarcolipin (SLN) is a regulator of the sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) pump and is critical in mediating muscle based thermogenesis and combating diet‐induced obesity. Unpublished work from our laboratory has shown that SLN may be important in maintaining muscle mass. Specifically, in phospholamban overexpressing mice (PlnOE), a mouse model that accurately recapitulates human centronuclear myopathy and exhibits severe muscle atrophy, we found that genetic deletion of Sln exaggerated the loss in soleus muscle size. As this reduction in muscle size was associated with a failure to promote type II fiber hypertrophy and fast‐to‐slow fiber type shifts, we questioned whether Sln deletion would also lead to similar defects in mechanically overloaded plantaris muscles that normally undergo comparable adaptations. To this end, we mechanically overloaded plantaris muscles from wild‐type (WT) and Sln‐null (SlnKO) mice for 2 weeks by performing soleus and gastrocnemius tenotomy. Strikingly, after 2 weeks of adaptation, the plantaris muscles from WT muscles displayed ectopic expression of SLN. This is particularly impressive since SLN's expression is typically restricted to slow‐oxidative muscles from the adult mouse. Furthermore, after two weeks of mechanical overload, the WT plantaris myofibers displayed significant hypertrophy (+22% to +48%, P < 0.0001) and fast‐to‐slow fiber type transitions with a significant increase in type I(P = 0.03) and type IIA (P = 0.05) fiber proportions, respectively; however, these adaptations to mechanical overload were not observed in SlnKO mice. Since calcineurin signaling is largely responsible for the cellular adaptations that occur with the mechanical overload stimulus, we examined the phosphorylation status of its well‐known substrate, nuclear factor of activated T‐cells (pNFAT). Strikingly, WT overloaded plantaris muscles showed significantly lower pNFAT compared with WT sham (−61%, P = 0.01), whereas pNFAT in overloaded SlnKO plantaris muscles was not significantly different from SlnKO sham (P = 0.11). Taken together, these results show for the first time, that SLN is recruited in mechanically overloaded plantaris muscles, and is critical in stimulating calcineurin‐mediated muscle growth and remodeling.Support or Funding InformationThis work was supported by the Canadian Institutes of Health Research (CIHR; MOP 86618 and MOP 47296 to A.R.T).