工程化骨骼肌肌束中肌内脂肪浸润的体外建模研究

Abstract

3D-printed micropillars enabled reproducible construction of engineered myobundles. • Engineered myobundles were used to mimic fat-infiltrated muscle without systemic confounding factors. • Intramuscular fat infiltration impairs muscle function through inflammation, matrix remodeling, and metabolic reprogramming. • Vitamin D intervention alleviates muscle impairments induced by fat infiltration. Intramuscular adipose tissue (IMAT) infiltration is primarily induced by aging, trauma, metabolic disorders, which is associated with various musculoskeletal diseases. However, a model that can simulate the pathological changes of this disease is lacking. In this manuscript, we developed an engineered skeletal muscle myobundle that enables the recapitulation of physiological structure, function, and contractile force in vitro. Human primary myoblasts were seeded into PDMS molds containing 3D-printed micropillars. After induced myogenic differentiation, myobundles with physiological structure and function were generated between the micropillars. By co-culturing with adipocyte spheroids derived from mesenchymal stem cells, IMAT-infiltrated myobundles can be recapitulated in vitro. With this model, we demonstrate that IMAT infiltration leads to structural and functional deterioration of the engineered myobundles. Transcriptomic analysis revealed IMAT-induced alterations in gene expression of myobundle, involving immune activation, extracellular matrix remodeling, and metabolic reprogramming. Moreover, vitamin D intervention markedly improved both the structural integrity and contractile performance of IMAT-infiltrated myobundles. This work establishes a physiologically relevant model of IMAT-infiltrated myobundles, offering a promising platform for mechanistic investigation and therapeutic evaluation in human skeletal muscle. Download: Download high-res image (196KB) Download: Download full-size image