Spatial-Bioenergetic-Immune Axis in Type 2 Diabetes Mellitus-Associated Sarcopenia: A Review from Pathogenesis to...

Type 2 diabetes mellitus (T2DM)-associated sarcopenia extends beyond isolated metabolic dysregulation; consequently, standard glucose-centric therapeutic strategies are insufficient to arrest myofibrillar atrophy. In this review, we characterize this pathogenesis through a novel spatial-bioenergetic-immune axis, stratifying disease progression across three hierarchical levels. First, within the tissue niche, the proliferation of CD90⁺ fibro-adipogenic progenitors (FAPs) establishes a pro-inflammatory microenvironment, driving extracellular matrix fibrosis that physically constrains the myogenic niche. Second, at the subcellular organelle level, kinase-driven structural disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) induces calcium dyshomeostasis and oxidative stress, culminating in bioenergetic collapse and NLRP3 inflammasome assembly. Third, at the immune-nuclear axis, retrograde signaling-exacerbated by GSDMD-mediated sarcolemmal permeabilization-induces sustained transcriptional repression of core myogenic programs. Synthesizing these spatial mechanisms, we propose a comprehensive clinical paradigm. By integrating microenvironmental modulation (SGLT2 inhibitors/GLP-1RAs), structural mechanotransduction (HIIT), and epigenetic rejuvenation (15-PGDH inhibitors), we advocate for a transition toward precision clinical management of T2DM-associated sarcopenia, aimed at arresting skeletal muscle degeneration and preserving physical functional capacity.