Single‐Nucleus Atlas of Spinal Sarcopenia Patients Reveals Disruption of Quiescent and Regenerative Satellite Cell Niches in Fatty‐Infiltrated Muscle

Abstract

ABSTRACT Severe muscle fat infiltration is a contributing factor to muscle loss, particularly in the spinal sarcopenia population. However, the underlying mechanism largely remains elusive. Here, we identified the intramuscular fat fraction (IMFF), rather than perimuscular fat fraction, as an independent determinant of trunk muscle strength. Individuals with higher IMFF (10‐15% and >15%) exhibited significantly lower paraspinal muscle mass and strength compared to those with lower IMFF (<5%). Using single‐nucleus RNA sequencing, we established the first cellular atlas of fat‐infiltrated paraspinal muscle, revealing profound remodeling of muscle architecture, extracellular matrix organization, and satellite cell niches. Among the adipose‐derived factors, ANGPTL4 emerged as a key paracrine suppressor of myogenesis, acting through upregulation of syndecan‐2 (SDC2) in satellite cells. Inhibition of SDC2 partially rescued ANGPTL4‐induced myogenic impairment in C2C12 cells. Furthermore, we identified a GPC3 + fibro/adipogenic progenitor (FAP) subpopulation with enhanced lipogenic potential, characterized by high expression of GPC3, PPARG, ADIPOQ, and FABP4, representing a transition from MME high GPC3 low FAPs into MME low GPC3 high adipogenic FAPs. Collectively, our findings delineate the cellular landscape and signaling interactions that underlie pathological fat infiltration in spinal muscles, providing mechanistic insight and potential therapeutic targets for spinal sarcopenia.