A Microphysiological Interface of Skeletal Myobundles and Inflamed Adipose Tissue for Recapitulating Muscle Dysfunction in an Obese Microenvironment

Systemic inflammation associated with obesity impairs skeletal muscle function through paracrine signaling from intermuscular adipose tissue-adipose depots situated between adjacent skeletal muscle groups-as well as from visceral adipose tissue, which consist of infiltrating macrophages surrounding inflamed adipocytes. These signals disrupt metabolic homeostasis and reduce muscle contractility, yet existing models are limited in their ability to recapitulate the crosstalk between skeletal muscle and inflamed adipose tissue in a physiologically relevant context. To address this, a human cell-based microphysiological system is developed that combines engineered muscle tissue (EMT) with an inflamed adipose-macrophage co-culture (IAMC) to model obesity-associated muscle dysfunction. EMTs, derived from human myoblasts on micropillar devices, self-assembled into 3D contractile myobundles. IAMC are generated by co-culturing inflamed adipocytes with pro-inflammatory M1-polarized macrophages, thereby recapitulating the obese inflammatory microenvironment. EMT-IAMC co-culture significantly reduced muscle contractility. Furthermore, cytokine profiling revealed elevated levels of pro-inflammatory mediators, and transcriptomic analysis showed metabolic reprogramming in EMTs, including upregulation of genes linked to fatty acid transport and insulin resistance. Collectively, these findings underscore the detrimental effects of inflamed adipose tissue on skeletal muscle function and suggest the potential utility of an interfaced platform for studying adipose-muscle interactions and screening therapies for obesity-related muscle dysfunction.