1. Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles.
- Author
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Swiderski K, Naim T, Trieu J, Chee A, Herold MJ, Kueh AJ, Goodman CA, Gregorevic P, and Lynch GS
- Subjects
- Animals, Phosphorylation, Mice, Male, Muscle Denervation methods, Mice, Inbred C57BL, Muscular Atrophy metabolism, Muscular Atrophy pathology, Muscular Atrophy genetics, Muscle, Skeletal metabolism, Muscle, Skeletal innervation, Muscle, Skeletal pathology, Dystrophin metabolism, Dystrophin genetics
- Abstract
The dystrophin protein has well-characterized roles in force transmission and maintaining membrane integrity during muscle contraction. Studies have reported decreased expression of dystrophin in atrophying muscles during wasting conditions, and that restoration of dystrophin can attenuate atrophy, suggesting a role in maintaining muscle mass. Phosphorylation of S3059 within the cysteine-rich region of dystrophin enhances binding between dystrophin and β-dystroglycan, and mimicking phosphorylation at this site by site-directed mutagenesis attenuates myotube atrophy in vitro. To determine whether dystrophin phosphorylation can attenuate muscle wasting in vivo, CRISPR-Cas9 was used to generate mice with whole body mutations of S3059 to either alanine (DmdS3059A) or glutamate (DmdS3059E), to mimic a loss of, or constitutive phosphorylation of S3059, on all endogenous dystrophin isoforms, respectively. Sciatic nerve transection was performed on these mice to determine whether phosphorylation of dystrophin S3059 could attenuate denervation atrophy. At 14 days post denervation, atrophy of tibialis anterior (TA) but not gastrocnemius or soleus muscles, was partially attenuated in DmdS3059E mice relative to WT mice. Attenuation of atrophy was associated with increased expression of β-dystroglycan in TA muscles of DmdS3059E mice. Dystrophin S3059 phosphorylation can partially attenuate denervation-induced atrophy, but may have more significant impact in less severe modes of muscle wasting., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)
- Published
- 2024
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