title: Alternative Splicing of Four Trafficking Genes Regulates Myofiber Structure and Skeletal Muscle Physiology.
abstract: During development, transcriptional and post-transcriptional networks are coordinately regulated to drive organ maturation. Alternative splicing contributes by producing temporal-specific protein isoforms. We previously found that genes undergoing splicing transitions during mouse postnatal heart development are enriched for vesicular trafficking and membrane dynamics functions. Here, we show that adult trafficking isoforms are also expressed in adult skeletal muscle and hypothesize that striated muscle utilizes alternative splicing to generate specific isoforms required for function of adult tissue. We deliver morpholinos into flexor digitorum brevis muscles in adult mice to redirect splicing of four trafficking genes to the fetal isoforms. The splicing switch results in multiple structural and functional defects, including transverse tubule (T-tubule) disruption and dihydropyridine receptor alpha (DHPR) and Ryr1 mislocalization, impairing excitation-contraction coupling, calcium handling, and force generation. The results demonstrate a previously unrecognized role for trafficking functions in adult muscle tissue homeostasis and a specific requirement for the adult splice variants.
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Cell Biology and Physiology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jimena_giudice@med.unc.edu.
authors.forename: Jimena
authors.initials: J
authors.lastname: Giudice
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Loehr
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: tcooper@bcm.edu.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D000375:Aging / Q000378:metabolism; D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D060172:Morpholinos / Q000494:pharmacology; D018485:Muscle Fibers, Skeletal / Q000502:physiology* / Q000648:ultrastructure; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D060172:Morpholinos; D009124:Muscle Proteins; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium
keywords: Cltc; Snap23; T-tubules; Tmed2; Trip10; alternative splicing; muscle; trafficking