Dataset Information

ITRAQ Protemics of mdx vs. mdx/Actg1-TG mouse skeletal muscle

ABSTRACT: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by deleterious mutations in the DMD gene, rendering non-functional forms or complete absence of the protein dystrophin. Eccentric contraction-induced force loss is the most robust and reproducible phenotype of dystrophin-deficient skeletal muscle, yet the molecular mechanisms underlying force loss remain obscure. To this end, we utilized the mdx mouse model of DMD, which displays extreme sensitivity to eccentric contractions. An existing mouse line from our lab that overexpresses cytoplasmic gamma-actin specifically in skeletal muscle (mdx/Actg1-TG) was shown to significantly protect mdx muscle against contraction-induced force loss. To understand the mechanism behind this protection, we performed iTRAQ proteomics on mdx/Actg1-TG tibialis anterior (TA) muscle versus non-transgenic littermate controls to identify differentially-expressed proteins that may afford protection upon gamma-actin overexpression.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle

DISEASE(S): Duchenne Muscular Dystrophy

SUBMITTER: James Ervasti

LAB HEAD: James M. Ervasti

PROVIDER: PXD009680 | Pride | 2018-10-22

REPOSITORIES: Pride

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			Action	DRS
	jervasti_oltho007_101013_13441_iTQ2_musc_09_25.raw	Raw
	jervasti_oltho007_101013_13441_iTQ2_musc_10_26.raw	Raw
	jervasti_oltho007_101013_13441_iTQ2_musc_11_27.raw	Raw
	jervasti_oltho007_101013_13441_iTQ2_musc_12_28.raw	Raw
	jervasti_oltho007_101013_13441_iTQ2_musc_13_29.raw	Raw

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Publications

Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle.

Olthoff John T JT Lindsay Angus A Abo-Zahrah Reem R Baltgalvis Kristen A KA Patrinostro Xiaobai X Belanto Joseph J JJ Yu Dae-Yeul DY Perrin Benjamin J BJ Garry Daniel J DJ Rodney George G GG Lowe Dawn A DA Ervasti James M JM

Nature communications 20181130 1

Force loss in skeletal muscle exposed to eccentric contraction is often attributed to injury. We show that EDL muscles from dystrophin-deficient mdx mice recover 65% of lost force within 120 min of eccentric contraction and exhibit minimal force loss when the interval between contractions is increased from 3 to 30 min. A proteomic screen of mdx muscle identified an 80% reduction in the antioxidant peroxiredoxin-2, likely due to proteolytic degradation following hyperoxidation by NADPH Oxidase 2. ...[more]

PMID: 30504831

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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.