315P Cardio-metabolic and cytoskeletal proteomic signatures differentiate fear sensitivity in dystrophin-deficient mdx mice

• Published in: Neuromuscular disorders : NMD Vol. 43; p. 104441
• Main Authors: Major, G., Herbold, C., Cheng, F., Lee, A., Russell, A., Lindsay, A.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01-10-2024
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.519

Extreme heterogeneity exists in the hypersensitive fear response exhibited by the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. Because fear hypersensitivity can impact dystrophic phenotypes, this research aimed to understand the central pathways driving this inter-individual variability. Male and female mdx mice were phenotypically stratified into “stress-resistant” or “stress-sensitive” groups based on their response to two stressors (scruff-restraint and forced treadmill exercise). Label-free quantitative proteomics of striated muscle (heart and tibialis anterior) revealed clustering of the proteome according to sex and stress sensitivity. In both muscles, stress-resistant females were most dissimilar from all other groups, with over 250 proteins differentially regulated between stress-resistant and stress-sensitive females in each muscle. Males showed less proteomic variation with stress sensitivity (70-90 proteins in each tissue) however these changes were associated with clear pathway enrichment. In the heart, stress-sensitive males had significant enrichment of pathways related to mitochondrial ATP synthesis, suggesting that increased cardio-metabolic capacity is associated with fear sensitivity in male mdx mice. Independent of striated muscle source or sex, fear sensitivity was associated with altered expression of beta-actin-like protein 2 (ACTBL2), an actin isoform critical for the formation of focal adhesions and cell motility. Stress-sensitive individuals had ∼6-fold higher expression of ACTBL2, indicative of altered cytoskeletal organisation and focal adhesion formation. Despite identifying proteomic signatures associated with fear sensitivity, no differences in the serum metabolome were detected acutely after a stressor. These data suggest that the heterogeneity in fear hypersensitivity in mdx mice is partially driven by cytoskeletal organisation, but that sex-specific cardio-metabolic reprogramming may play a role in this phenotype.