Sarcolipin is Upregulated in Response to Soleus Unloading Caused by Tenotomy and Opposes Muscle Atrophy

Abstract

Previous studies have shown that sarcolipin (SLN), a small inhibitor of the sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) pump, is upregulated in conditions of muscle atrophy. To date, however, the role of SLN in muscle atrophy remains unknown. In another unpublished study from our laboratory, we mechanically overloaded plantaris muscles by performing soleus and gastrocnemius tenotomy (surgical transection of the tendon), and found that SLN is critical in mediating muscle growth and fiber type remodeling. In this study we questioned the role of SLN in the tenotomized soleus, which is a model of muscle unloading known to cause muscle degeneration, atrophy, and a fast‐glycolytic muscle phenotype. We hypothesized that in the absence of Sln, soleus muscles would exhibit greater muscle atrophy and an accelerated slow‐to‐fast fiber type shift. Our results show that 2 weeks after tenotomy, SLN protein was upregulated 14‐fold (P ≤ 0.05) in WT muscle compared with sham. Furthermore, removing this 14‐fold upregulation led to a greater percent reduction in soleus muscle mass relative to body weight in SlnKO mice compared with WT (WT, −51.0 ± 3.5% vs. SlnKO, −59.0 ± 1.8%, P ≤ 0.05). In addition, significant reductions in myofiber cross‐sectional area were found in WT mice (−29% to −38%, P ≤ 0.05, two‐way repeated ANOVA), and also in SlnKO mice, but perhaps to a greater extent (−33% to −42%, P ≤ 0.05, two‐way repeated ANOVA). With respect to the slow‐to‐fast fiber type shift, the WT mice exhibited a partial shift in response to tenotomy with a significant decrease and trending increase in type IIA (P ≤ 0.05) and type IIX (P = 0.10) fiber percent, respectively. In contrast, in response to tenotomy, SlnKO mice exhibited an accelerated slow‐to‐fast fibre type shift with a significant decrease in type I (P ≤ 0.05) and increase in type IIX (P ≤ 0.05) fiber percent, respectively. Since calcineurin stabilizes the deleterious effects of reduced mechanical loading, we examined the phosphorylation status of its well‐known substrate nuclear factor of activated T‐cell (pNFAT). Our results show that, in response to tenotomy, WT soleus muscles had significantly lower pNFAT compared with sham (−57%, P ≤ 0.05); however pNFAT was not different between SlnKO sham and tenotomized soleus muscles. Thus, our results show that SLN upregulation in tenotomized soleus muscles is required to counteract muscle atrophy and the transition to the fast, glycolytic fiber phenotype, and may do so through its stimulatory effect on calcineurin.Support or Funding InformationThis work was supported by the Canadian Institutes of Health Research (CIHR; MOP 86618 and MOP 47296 to A.R.T).