A smooth muscle knock-out mouse model unexpectedly reveals a potential novel role for βENaC in striated muscle growth and/or remodeling

The epithelial Na + channel β subunit (βENaC) is a member of the evolutionarily conserved family of degenerin proteins linked to mechanotransduction. βENaC is expressed in vascular smooth muscle cells (VSMCs), where it is essential for pressure-induced constriction (PIC) of small renal and cerebral arteries. We generated a smooth muscle βENaC knock-out using Cre-lox technology (SM22-Cre; βENaC floxed mice) to study the importance of βENaC in PIC responses and contribution to end-organ vascular injury. As expected, deletion of smooth muscle βENaC (SMC-βENaC-/-) abolished renal PIC responsiveness, leading to mild renal hypertrophy and injury, as well as a modest increase in systemic blood pressure by 26 weeks of age. Unexpectedly, the SMC-βENaC-/- mice displayed lower body masses (male, 35.3 ± 0.5 vs 33.7 ± 0.7 g; female, 26.1 ± 0.7 vs 24.1 ± 0.5, p (genotype)=0.004) with no differences in body or tibial length, and a lack of cardiac remodeling in response to elevated blood pressure. These findings raise the possibility of inappropriate growth and/or remodeling in the SMC-βENaC-/- model. Although SM22 expression is robust in smooth muscle, it is also expressed in other tissues at lower levels. Thus, we questioned whether loss of βENaC in striated muscle may contribute to the phenotype. Using public RNAseq databases, published literature, and qPCR of muscle samples, we determined SM22 and βENaC are expressed in striated muscle, including the gastrocnemius, soleus, and left ventricle, confirming that loss of striated muscle βENaC may occur in our SMC-βENaC-/- model. We examined cardiac function and body composition in a separate group of mice (14-17 weeks old) using echocardiography and EchoMRI, respectively. SMC-βENaC-/- mice had lower left ventricle masses, but no changes in diastolic or systolic function indicators. SMC-βENaC-/- male mice had decreased lean mass (28.2 ± 0.5 vs 26.1 ± 0.6 g; p = 0.02), but similar fat mass. We identified a similar pattern of reduced body and lean masses in 16-week-old βENaC hypomorph mice ( https://doi.org/10.3390/biology14111558 ). Further analysis of muscle injury markers from plasma samples in 26-week-old mice indicates that creatine kinase, AST, and the AST/ALT ratio were higher in SMC-βENaC-/-. Plasma ALT and LDH were not different, suggesting striated muscle stress rather than overt injury. Since degenerin channels transduce mechanical signals in VSMCs, our findings raise the possibility that βENaC may play a similar role in striated muscle, perhaps in muscle growth and remodelling in response to external mechanical forces (i.e., gravity, blood pressure). Planned studies will examine striated muscle structure, fat/lean composition, exercise capacity, and muscle strength in cardiac and skeletal muscle-specific βENaC knock-out mice. Support provided by: R01DK137167, P30GM149404, P20GM104357, and P20GM121334. 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.