Key result
Redirecting four trafficking genes to fetal isoforms in mice impairs excitation-contraction coupling and force generation.
Why the study?
Alternative splicing of trafficking genes during development produces isoforms that may be required for adult striated muscle function, but their role in adult muscle physiology is unclear.
Does redirecting splicing of trafficking genes to fetal isoforms impair adult skeletal muscle structure and function in mice?
Does redirecting splicing of trafficking genes to fetal isoforms impair adult skeletal muscle structure and function in mice?
Alternative splicing of trafficking genes to adult isoforms is required for maintaining adult skeletal muscle structure and function.
Adult isoforms shared across striated muscle; leaves open coordinated splicing roles in maturation without clinical implications yet.
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.
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Giudice et al. (2016) studied Skeletal muscle physiology. Morpholinos targeting four trafficking genes was evaluated on Structural and functional defects including T-tubule disruption and impaired excitation-contraction coupling. Redirecting splicing of four trafficking genes to fetal isoforms in adult mice caused structural and functional defects, impairing excitation-contraction coupling, calcium handling, and force generation.
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