Dataset Information

Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance.

ABSTRACT: Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. 'Diversity Outbred in Australia (DOz)' is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle's contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focusing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform and in vitro assays of insulin action using the Prestwick chemical library. These complementary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation in ex vivo insulin-resistant mouse muscle and palmitate-induced insulin-resistant myotubes demonstrated potent insulin action restoration, potentially via upregulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems-level analysis by identifying potential therapeutics for insulin resistance.

SUBMITTER: Masson SWC

PROVIDER: S-EPMC10371229 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance.

Masson Stewart W C SWC Madsen Søren S Cooke Kristen C KC Potter Meg M Vegas Alexis Diaz AD Carroll Luke L Thillainadesan Senthil S Cutler Harry B HB Walder Ken R KR Cooney Gregory J GJ Morahan Grant G Stöckli Jacqueline J James David E DE

eLife 20230726

Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. 'Diversity Outbred in Australia (DOz)' is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle's contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that asso ...[more]

PMID: 37494090

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Project description:Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most prevalent forms of the chronic and progressive pathological condition known as cardiomyopathy. These diseases have different aetiologies; however, they share the feature of haemodynamic abnormalities, which is mainly due to dysfunction in the contractile proteins that make up the contractile unit known as the sarcomere. To date, pharmacological treatment options are not disease-specific and rather focus on managing the symptoms, without addressing the disease mechanism. Earliest attempts at improving cardiac contractility by modulating the sarcomere indirectly (inotropes) resulted in unwanted effects. In contrast, targeting the sarcomere directly, aided by high-throughput screening systems, could identify small molecules with a superior therapeutic value in cardiac muscle disorders. Herein, an extensive literature review of 21 small molecules directed to five different targets was conducted. A simple scoring system was created to assess the suitability of small molecules for therapy by evaluating them in eight different criteria. Most of the compounds failed due to lack of target specificity or poor physicochemical properties. Six compounds stood out, showing a potential therapeutic value in HCM, DCM or heart failure (HF). Omecamtiv Mecarbil and Danicamtiv (myosin activators), Mavacamten, CK-274 and MYK-581 (myosin inhibitors) and AMG 594 (Ca2+-sensitiser) are all small molecules that allosterically modulate troponin or myosin. Omecamtiv Mecarbil showed limited efficacy in phase III GALACTIC-HF trial, while, results from phase III EXPLORER-HCM trial were recently published, indicating that Mavacamten reduced left ventricular outflow tract (LVOT) obstruction and diastolic dysfunction and improved the health status of patients with HCM. A novel category of small molecules known as "recouplers" was reported to target a phenomenon termed uncoupling commonly found in familial cardiomyopathies but has not progressed beyond preclinical work. In conclusion, the contractile apparatus is a promising target for new drug development.

Dataset Information

Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance.

Publications

Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance.

Similar Datasets

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