Syntaxin 4 is the newest culprit for muscular dystrophy

Muscular dystrophies are a group of genetic disorders characterized by progressive skeletal muscle degeneration and weakness that culminates in the replacement of damaged muscle with fibrotic and non-muscular tissue. Majority of muscular dystrophies are attributed to mutations in proteins for sarcolemma repair, stability and/or extracellular matrix (ECM) linkage such as Dystrophin for Duchenne Muscular Dystrophy (DMD). Our recent studies revealed new findings indicating the important role of Syntaxin 4 (STX4) in the structural maintenance of skeletal muscle integrity, in addition to its known functions as a sarcolemma and mitochondrial localized SNARE protein required for glucose uptake and mitochondrial homeostasis. A doxycycline-inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mouse model revealed marked bodyweight loss attributable to reduction of skeletal muscle mass in both male and female adult cohorts. We hypothesized that STX4 ablation leads to muscular dystrophy via a novel role in maintaining the integrity of skeletal muscle sarcolemma. Histological analysis of skmSTX4-iKO quadriceps muscle revealed 1) substantial degenerative muscle fibers along with regenerative repair, 2) accumulation of inflammatory infiltrates and 3) adipose tissue replacement in skmSTX4-iKO mice, characteristic features of a muscular dystrophy phenotype. These dystrophic changes were further supported by increased leakage of muscle protein creatine kinase in the serum of skmSTX4-iKO mice, an established standard test for clinical diagnosis of muscular dystrophy and elevated inflammatory and fibrosis markers, leading to impaired grip strength. Importantly, loss of STX4 resulted in reduced cell surface presence of Integrin beta-1, a protein critical for maintaining the sarcolemma-ECM linkage in skmSTX4-iKO mouse muscle. Furthermore, siRNA mediated knockdown of STX4 in human LHCN-M2 myotube cell lines also led to reduced cell surface presence of Integrin beta-1, suggesting the direct involvement of STX4 in maintaining sarcolemma integrity. Collectively, our findings demonstrate the requirement of STX4 in maintaining skeletal muscle sarcolemma integrity and identify loss of STX4 as a new player in muscular dystrophy. This work is supported by grants from the National Institutes of Health (DK067912, DK112917 and DK102233) and the City of Hope Arthur Riggs Diabetes & Metabolism Research Institute 2026 Innovation Award. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.