Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles

• Published in: Physiological reports Vol. 12; no. 13; pp. e16145 - n/a
• Main Authors: Swiderski, Kristy, Naim, Timur, Trieu, Jennifer, Chee, Annabel, Herold, Marco J., Kueh, Andrew J., Goodman, Craig A., Gregorevic, Paul, Lynch, Gordon S.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2024; Wiley
• Subjects: Animals; Atrophy; Biological research; CRISPR; Denervation; Dystroglycan; Dystrophin; Dystrophin - genetics; Dystrophin - metabolism; Isoforms; Localization; Male; Membrane proteins; Mice; Mice, Inbred C57BL; muscle atrophy; Muscle contraction; Muscle Denervation - methods; Muscle, Skeletal - innervation; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular dystrophy; Musculoskeletal system; Myotubes; Phosphorylation; Protein expression; Protein synthesis; Proteins; S3059; Sciatic nerve; Site-directed mutagenesis; Skeletal muscle; Surgery; Fiji; Melbourne Victoria Australia; Australia; United States > US; dystrophin; muscle atrophy; denervation; S3059; phosphorylation
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.16145

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. Mice expressing systemic phospho‐null (DmdS3059A) or phosphomimetic (DmdS3059E) mutation of the dystrophin protein were generated using CRISPR/Cas9 technology and subjected to sciatic nerve transection. Denervation‐induced atrophy was partially attenuated in the tibialis anterior muscles of mice expressing the DmdS3059E mutation. Attenuation of atrophy was associated with increased expression of β‐dystroglycan. Dystrophin S3059 phosphorylation can partially attenuate denervation‐induced atrophy, but may have more significant impact in less severe modes of muscle wasting. Created with BioRender.com.