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. 2025 Feb 1:362:123343.
doi: 10.1016/j.lfs.2024.123343. Epub 2024 Dec 29.

Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia

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Free article

Altering phosphorylation of dystrophin S3059 to attenuate cancer cachexia

Kristy Swiderski et al. Life Sci. .
Free article

Abstract

Aims: Cancer cachexia affects up to 80 % of patients with advanced cancer and accounts for >20 % of all cancer-related deaths. Sarcolemmal localization of dystrophin, a key protein within the dystrophin-glycoprotein complex (DGC), is perturbed in multiple muscle wasting conditions, including cancer cachexia, indicating a potential role for dystrophin in the maintenance of muscle mass. Strategies to preserve dystrophin expression at the sarcolemma might therefore combat muscle wasting. Phosphorylation of dystrophin serine 3059 (S3059) enhances the interaction between dystrophin and β-dystroglycan and attenuates atrophy of mouse muscle myotubes in vitro when cultured in the presence of colon-26 (C-26) cancer cells. Whether dystrophin S3059 phosphorylation can attenuate cachexia in tumor-bearing mice has not been determined.

Materials and methods: Mice with systemic mutations of serine 3059 to alanine (DmdS3059A; phospho-null) or glutamate (DmdS3059E; phosphomimetic) were generated to investigate the impact of S3059 phosphorylation on survival and skeletal muscle health in the C-26 tumor-bearing mouse model of cancer cachexia using measures of skeletal muscle function in situ combined with biochemical and histological assessments.

Key findings: In a model of mild cachexia, loss of skeletal muscle mass and function was greater in DmdS3059A mice. Conversely, in a model of severe cachexia, overall survival was prolonged, and markers of protein degradation were decreased in skeletal muscles of DmdS3059E mice. Thus, manipulating dystrophin S3059 phosphorylation can alter the progression of cachexia in tumor-bearing mice.

Significance: Strategies to increase phosphorylation of this site, and/or increase dystrophin protein expression, have therapeutic potential for cancer cachexia.

Keywords: Cancer cachexia; Dystrophin; Dystrophin-glycoprotein complex; Mouse; Phosphorylation; S3059; Skeletal muscle.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no conflict of interest.