Matrisome proteomics reveals novel mediators of muscle remodeling with aerobic exercise training.

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Phenotypic changes in muscle that occur with training such as a switch to a more oxidative fiber type, and increased capillary density contribute to the well-known health benefits of aerobic exercise. The muscle matrisome likely plays an important role in muscle remodeling with exercise. However, due to technical limitations in studying muscle ECM proteins, which are highly insoluble, little is known about the muscle matrisome and how it contributes to muscle remodeling. Here, we utilized two-fraction methodology to extract muscle proteins, combined with multiplexed tandem mass tag proteomic technology to identify 161 unique ECM proteins in mouse skeletal muscle. In addition, we demonstrate that aerobic exercise training induces remodeling of a significant proportion of the muscle matrisome. We performed follow-up experiments to validate exercise-regulated ECM targets in a separate cohort of mice using Western blotting and immunofluorescence imaging. Our data demonstrate that changes in several key ECM targets are strongly associated with muscle remodeling processes such as increased capillary density in mice. We also identify LOXL1 as a novel muscle ECM target associated with aerobic capacity in humans. In addition, publically available data and databases were used for in silico modeling to determine the likely cellular sources of exercise-induced ECM remodeling targets and identify ECM interaction networks. This work greatly enhances our understanding of ECM content and function in skeletal muscle and demonstrates an important role for ECM remodeling in the adaptive response to exercise. The raw MS data have been deposited to the ProteomeXchange with identifier PXD053003.", "claims": [{"id": "claim-method", "statement": "Proteins were tested for differential expression between exercise and control using moderated t-tests from the R package Limma [73].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39220302", "locator": "sections[14] \"Matrisome annotation and quantification\" paragraph 3", "quote": "Proteins were tested for differential expression between exercise and control using moderated t-tests from the R package Limma [73]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data will be made available on request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:39220302", "locator": "sections[27] \"Data availability\" paragraph 2", "quote": "Data will be made available on request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Using our newly optimized ECM enrichment and quantification methods, we found that exercise altered more than 34% of identified core matrisome proteins, with the majority being increased by training (Fig. 3A–B).", "kind": "quantitative", "target": {"value": 34.0, "unit": "per cent", "tolerance": null, "source": "Using our newly optimized ECM enrichment and quantification methods, we found that exercise altered more than 34% of identified core matrisome proteins, with the majority being increased by training (Fig. 3A–B)."}, "evidence": [{"asset": "source:pmid:39220302", "locator": "sections[2] \"Results\" paragraph 5", "quote": "Using our newly optimized ECM enrichment and quantification methods, we found that exercise altered more than 34% of identified core matrisome proteins, with the majority being increased by training (Fig. 3A–B)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Using our newly optimized ECM enrichment and quantification methods, we found that exercise altered more than 34% of identified core matrisome proteins, with the majority being increased by training (Fig. 3A–B).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:39220302"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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We also identify LOXL1 as a novel muscle EC", "ology to identify 161 unique ECM proteins in mouse skeletal muscle. In addition, we demonstrate", "slin Diabetes Center. Male, 8-week-old, CD-1 mice were purchased from Charles River Laboratories (I", "from Charles River Laboratories (IGS; #022). Mice were group-housed in a pathogen-free facility and"], "order_basis": "paper_text_order:824", "id": "assay:1"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["M targets in a separate cohort of mice using Western blotting and immunofluorescence imaging. 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