Overexpression of sarcolipin (SLN), a regulator of sarco(endo)plasmic reticulum Ca-ATPases (SERCAs), stimulates calcineurin signaling to enhance skeletal muscle oxidative capacity. Some studies have shown that calcineurin may also control skeletal muscle mass and remodeling in response to functional overload and unload stimuli by increasing myofiber size and the proportion of slow fibers. To examine whether SLN might mediate these adaptive responses, we performed soleus and gastrocnemius tenotomy in wild-type (WT) and -null () mice and examined the overloaded plantaris and unloaded/tenotomized soleus muscles. In the WT overloaded plantaris, we observed ectopic expression of SLN, myofiber hypertrophy, increased fiber number, and a fast-to-slow fiber type shift, which were associated with increased calcineurin signaling (NFAT dephosphorylation and increased stabilin-2 protein content) and reduced SERCA activity. In the WT tenotomized soleus, we observed a 14-fold increase in SLN protein, myofiber atrophy, decreased fiber number, and a slow-to-fast fiber type shift, which were also associated with increased calcineurin signaling and reduced SERCA activity. Genetic deletion of altered these physiological outcomes, with the overloaded plantaris myofibers failing to grow in size and number, and transition towards the slow fiber type, while the unloaded soleus muscles exhibited greater reductions in fiber size and number, and an accelerated slow-to-fast fiber type shift. In both the overloaded and unloaded muscles, these findings were associated with elevated SERCA activity and blunted calcineurin signaling. Thus, SLN plays an important role in adaptive muscle remodeling potentially through calcineurin stimulation, which could have important implications for other muscle diseases and conditions.

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy affecting 1 in 3500 live male births. Although there is no cure for DMD, therapeutic strategies aimed at enhancing calcineurin signalling and promoting the slow fibre phenotype have shown promise in mdx mice, which is the classical mouse model for DMD. Sarcolipin (SLN) is a small protein that regulates the sarco(endo)plasmic reticulum Ca2+-ATPase pump and its expression is highly upregulated in dystrophic skeletal muscle. We have recently shown that SLN in skeletal muscle amplifies calcineurin signalling thereby increasing myofibre size and the slow fibre phenotype. Therefore, in the present study we sought to determine the physiological impact of genetic Sln deletion in mdx mice, particularly on calcineurin signalling, fibre-type distribution and size and dystrophic pathology. We generated an mdx/Sln-null (mdx/SlnKO) mouse colony and hypothesized that the soleus and diaphragm muscles from these mice would display blunted calcineurin signalling, smaller myofibre sizes, an increased proportion of fast fibres and worsened dystrophic pathology compared with mdx mice. Our results show that calcineurin signalling was impaired in mdx/SlnKO mice as indicated by reductions in utrophin, stabilin-2 and calcineurin expression. In addition, mdx/SlnKO muscles contained smaller myofibres, exhibited a slow-to-fast fibre-type switch that corresponded with reduced expression of mitochondrial proteins and displayed a worsened dystrophic pathology compared with mdx muscles. Altogether, our findings demonstrate a critical role for SLN upregulation in dystrophic muscles and suggest that SLN can be viewed as a potential therapeutic target.

The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) pump is a major contributor to skeletal muscle Ca2+ homeostasis and metabolic rate. SERCA activity can become adaptively uncoupled by its regulator sarcolipin (SLN) to increase the energy demand of Ca2+ pumping, preventing excessive obesity and glucose intolerance in mice. Several other SERCA regulators bear structural and functional resemblance to SLN, including phospholamban (PLN). Here, we sought to examine whether endogenous levels of skeletal muscle PLN control SERCA Ca2+ pumping efficiency and whole body metabolism. Using PLN-null mice ( Pln−/−), we found that soleus (SOL) muscle’s SERCA pumping efficiency (measured as an apparent coupling ratio: Ca2+ uptake/ATP hydrolysis) was unaffected by PLN. Expression of Ca2+-handling proteins within the SOL, including SLN, were comparable between Pln−/− and wild-type (WT) littermates, as were fiber-type characteristics. Not surprisingly then, Pln−/− mice developed a similar degree of diet-induced obesity and glucose intolerance as WT controls when given a “Western” high-fat diet. Lack of an excessively obesogenic phenotype of Pln−/− could not be explained by compensation from skeletal muscle SLN or brown adipose tissue uncoupling protein-1 content. In agreement with several other reports, our study lends support to the notion that PLN serves a functionally distinct role from that of SLN in skeletal muscle physiology.

PurposeMedical students report higher levels of burnout, anxiety, and depression compared with age-matched peers. These mental health challenges have been linked to reduced workplace productivity, empathy, and professionalism. Yet, students experiencing mental health issues often decide not to access mental health resources, citing limited time and concerns about confidentiality, stigma, and the cost of private therapy. This study aimed to provide a framework for understanding barriers medical students face regarding access to mental health resources.