TY - JOUR T1 - The role of <em>Limch1</em> alternative splicing in skeletal muscle function JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201868 VL - 6 IS - 6 SP - e202201868 AU - Matthew S Penna AU - Rong-Chi Hu AU - George G Rodney AU - Thomas A Cooper Y1 - 2023/06/01 UR - https://www.life-science-alliance.org/content/6/6/e202201868.abstract N2 - Postnatal skeletal muscle development is a highly dynamic period associated with widespread alternative splicing changes required to adapt tissues to adult function. These splicing events have significant implications because the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIMCH1 is a stress fiber–associated protein that is alternatively spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle–specific isoform containing six additional exons simultaneously included after birth in the mouse. CRISPR/Cas9 was used to delete the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the predominantly fetal isoform, uLIMCH1. mLIMCH1 knockout mice had significant grip strength weakness in vivo, and maximum force generated was decreased ex vivo. Calcium-handling deficits were observed during myofiber stimulation that could explain the mechanism by which mLIMCH1 knockout leads to muscle weakness. In addition, LIMCH1 is mis-spliced in myotonic dystrophy type 1, with the muscleblind-like (MBNL) family of proteins acting as the likely major regulator of Limch1 alternative splicing in skeletal muscle. ER -