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Cardio-metabolic and cytoskeletal proteomic signatures differentiate stress hypersensitivity in dystrophin-deficient mdx mice

ABSTRACT: Extreme heterogeneity exists in the hypersensitive stress response exhibited by the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy. Because stress hypersensitivity can impact dystrophic phenotypes, this research aimed to understand the peripheral 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 laboratory stressors. Quantitative proteomics of striated muscle (heart and tibialis anterior) revealed clustering of the proteome according to sex and stress hypersensitivity. 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, 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 stress hypersensitivity in male mdx mice. Independent of striated muscle source or sex, stress hypersensitivity 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 higher expression of ACTBL2, indicative of altered cytoskeletal organisation. Despite identifying proteomic signatures associated with stress hypersensitivity, these did not correlate with differences in the serum metabolome acutely after a stressor. These data suggest that the heterogeneity in stress hypersensitivity in mdx mice is partially driven by cytoskeletal organisation, but that sex-specific cardio-metabolic reprogramming may also play a role in this phenotype

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Tibialis Anterior

DISEASE(S): Duchenne Muscular Dystrophy

SUBMITTER: Albert Lee

LAB HEAD: Albert Lee

PROVIDER: PXD052143 | Pride | 2024-12-28

REPOSITORIES: Pride

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			Action	DRS
	200706_Angus_muscle_Heart_SRF_103_R01.raw	Raw
	200706_Angus_muscle_Heart_SRF_103_R02.raw	Raw
	200706_Angus_muscle_Heart_SRF_103_R03.raw	Raw
	200706_Angus_muscle_Heart_SRF_121_R01.raw	Raw
	200706_Angus_muscle_Heart_SRF_121_R02.raw	Raw

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Project description:Duchenne muscular dystrophy (DMD) is characterized by impaired cytoskeleton organization, cytosolic calcium handling oxidative stress and mitochondrial dysfunction. This results in progressive and fatal muscle damage, wasting and weakness. The Striated Muscle activator of Rho signalling (STARS) is an actin binding protein that activates the myocardin-related transcription factor-A (MRTFA)/serum response factor (SRF) transcriptional pathway; a pathway that regulates cytoskeletal structure, muscle function, growth and repair. Here we investigated the regulation of several members of the STARS signalling pathway in muscle from patients with DMD and the dystrophin-deficient mdx and dko (utrophin‐ and dystrophin‐null) mice. A reduction in protein levels of STARS, SRF and RHOA, and an increase in MRTFA were observed in quadriceps muscle of patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in mdx tibialis anterior (TA) muscle and Srf and Mrtfa mRNAs were decreased in dko TA muscle. Overexpressing the human STARS (hSTARS) protein in mdx TA muscle increased maximal isometric specific force by 13%. This was not associated with changes in muscle mass, fibre cross-sectional area (CSA), fibre type, centralized nuclei or collagen deposition. Proteomics screening identified 31 upregulated and 22 downregulated proteins or individual peptides that were significantly regulated by hSTARS overexpression. Pathway enrichment analysis indicated that hSTARS overexpression regulated the keratin, NRF2 and oxidative phosphorylation (OXPHOS) pathways. These pathways are impaired in dystrophic muscle and regulate cytoskeleton organization, oxidative stress and mitochondrial energy production; processes that are vital for muscle function. We conclude that increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via its regulation of multiple pathways that positively influence cytoskeletal structure, oxidative stress and energy production.

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Cardio-metabolic and cytoskeletal proteomic signatures differentiate stress hypersensitivity in dystrophin-deficient mdx mice

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