[R01] Intramuscular fat and endocrine signaling in muscular dystrophy

Ente: National Institute of Arthritis and Musculoskeletal and Skin Diseases

Scadenza: 2030-06-30

Importo max: $381,527

Paese: US

Descrizione

Project Summary Progressive replacement of skeletal muscle with intramuscular adipose tissue (IMAT) is a defining feature of the dystrophinopathies, Duchenne (DMD) and Becker muscular dystrophy (BMD). Although IMAT accumulation is also observed in obesity and aging, in muscular dystrophy it arises through a distinct, non-metabolic mechanism and can replace entire muscles, creating a uniquely large adipose depot. Subcutaneous and visceral fat are well-established endocrine tissues whose adipokine secretion contributes to systemic metabolic dysfunction. However, the endocrine activity of IMAT, particularly in muscular dystrophy where its volume is massive, remains virtually unstudied. This represents a fundamental gap in understanding how muscle degeneration may influence whole-body metabolic health. Preliminary data from our group indicate that several circulating adipokines, including leptin and fatty acid binding protein 4, increase with disease severity in DMD and correlate strongly with MRI-based measures of muscle fat independent of age, BMI, and corticosteroid use. These findings suggest IMAT may function as an active endocrine tissue and a major source of circulating adipokines. Therefore, the aim of this project is to define the endocrine role of IMAT in dystrophinopathy and determine its potential systemic consequences. We hypothesize progressive IMAT accumulation secretes adipokines into systemic circulation and contributes to metabolic dysfunction, including hepatic steatosis. Leveraging two ongoing parent studies, we will integrate IMAT biopsies, quantitative MRI, and serum analyses in children and adults with dystrophinopathy. Aim 1 will establish that IMAT in dystrophinopathy secretes adipokines that enter systemic circulation by performing proteomics on IMAT biopsies from adults with BMD. Aim 2 will quantify the contribution of IMAT burden to circulating adipokine levels in DMD and BMD, determining whether IMAT expansion drives proportional increases in IMAT-derived adipokines. Exploratory Aim 3 will define relationships between IMAT, circulating adipokines, and hepatic steatosis using quantitative MRI to determine whether endocrine IMAT activity contributes to liver fat accumulation in dystrophinopathy. Establishing IMAT as an endocrine tissue would represent a paradigm shift in understanding metabolic dysfunction in muscular dystrophy, identifying a previously unrecognized mechanism linking muscle degeneration to systemic metabolism. Findings may reveal IMAT- derived adipokines as biomarkers or therapeutic targets and improve risk stratification for gene therapy–related hepatic toxicity. Istituzione: UNIVERSITY OF FLORIDA PI: Alison M Barnard Progetto: 1R01AR088153-01

Settori: National Institute of Arthritis and Musculoskeletal and Skin Diseases

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