SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism.

ABSTRACT

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (Lrrc8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. LRRC8A over-expression in Lrrc8a KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle-targeted Lrrc8a KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to wild-type (WT) mice. These results reveal that the LRRC8 complex regulates insulin-PI3K-AKT-mTOR signaling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.

Skeletal muscles ­ the force-generating tissue attached to bones ­ must maintain their mass and health for the body to work properly. It is therefore necessary to understand how an organism can regulate the way skeletal muscles form, grow and heal. A multitude of factors can control how muscles form, including mechanical signals. The molecules that can sense these mechanical stimuli, however, remain unknown. Mechanoresponsive ion channels provide possible candidates for these molecular sensors. These proteins are studded through the cell membranes, where they can respond to mechanical changes by opening and allowing the flow of ions in and out of a cell, or by changing interactions with other proteins. The SWELL1 protein is a component of an ion channel known as VRAC, which potentially responds to mechanical stimuli. This channel is associated with many biological processes such as cells multiplying, migrating, growing and dying, but it is still unclear how. Here, Kumar et al. first tested whether SWELL1 controls how skeletal muscle precursors mature into their differentiated and functional form. These experiments showed that SWELL1 regulates this differentiation process under the influence of the hormone insulin, as well as mechanical signals such as cell stretching. In addition, this work revealed that SWELL1 relies on an adaptor molecule called GRB2 to relay these signals in the cell. Next, Kumar et al. genetically engineered mice lacking SWELL1 only in skeletal muscle. These animals had smaller muscle cells, as well as muscles that were weaker and less enduring. When raised on a high-calorie diet, the mutant mice also got more obese and developed resistance to insulin, which is an important step driving obesity-induced diabetes. Together, these findings show that SWELL1 helps to regulate the formation and function of muscle cells, and highlights how an ion channel participates in these processes. Healthy muscles are key for overall wellbeing, as they also protect against obesity and obesity-related conditions such as type 2 diabetes or nonalcoholic fatty liver disease. This suggests that targeting SWELL1 could prove advantageous in a clinical setting.