Alternative Splicing of Four Trafficking Genes Regulates Myofiber Structure and Skeletal Muscle Physiology

Cell Rep. 2016 Nov 15;17(8):1923-1933. doi: 10.1016/j.celrep.2016.10.072.


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.

Keywords: Cltc; Snap23; T-tubules; Tmed2; Trip10; alternative splicing; muscle; trafficking.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Alternative Splicing / drug effects
  • Alternative Splicing / genetics*
  • Animals
  • Biomechanical Phenomena
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Male
  • Mice
  • Models, Biological
  • Morpholinos / pharmacology
  • Muscle Fibers, Skeletal / physiology*
  • Muscle Fibers, Skeletal / ultrastructure
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport / drug effects
  • Ryanodine Receptor Calcium Release Channel / metabolism


  • Calcium Channels, L-Type
  • Morpholinos
  • Muscle Proteins
  • Protein Isoforms
  • Ryanodine Receptor Calcium Release Channel
  • Calcium