Fibro-adipogenic progenitors in physiological adipogenesis and intermuscular adipose tissue remodeling

Abstract

Excessive accumulation of intermuscular adipose tissue (IMAT) is a common pathological feature in various metabolic and health conditions and can cause muscle atrophy, reduced function, inflammation, insulin resistance, cardiovascular issues, and unhealthy aging. Although IMAT results from fat accumulation in muscle, the mechanisms underlying its onset, development, cellular components, and functions remain unclear. IMAT levels are influenced by several factors, such as changes in the tissue environment, muscle type and origin, extent and duration of trauma, and persistent activation of fibro-adipogenic progenitors (FAPs). FAPs are a diverse and transcriptionally heterogeneous population of stromal cells essential for tissue maintenance, neuromuscular stability, and tissue regeneration. However, in cases of chronic inflammation and pathological conditions, FAPs expand and differentiate into adipocytes, resulting in the development of abnormal and ectopic IMAT. This review discusses the role of FAPs in adipogenesis and how they remodel IMAT. It highlights evidence supporting FAPs and FAP-derived adipocytes as constituents of IMAT, emphasizing their significance in adipose tissue maintenance and development, as well as their involvement in metabolic disorders, chronic pathologies and diseases. We also investigated the intricate molecular pathways and cell interactions governing FAP behavior, adipogenesis, and IMAT accumulation in chronic diseases and muscle deconditioning. Finally, we hypothesize that impaired cellular metabolic flexibility in dysfunctional muscles impacts FAPs, leading to IMAT. A deeper understanding of the biology of IMAT accumulation and the mechanisms regulating FAP behavior and fate are essential for the development of new therapeutic strategies for several debilitating conditions.

Keywords: Adipocytes; Adipogenesis; FAPs; IMAT; Metabolism; Obesity; Skeletal muscle.

Fig. 1.

IMAT deposition, a hallmark of chronic fatty infiltration, is exacerbated in a variety of debilitating and chronic human diseases and injuries. This illus - tration highlights the diverse range of pathologies in which IMAT deposition is implicated, including unhealthy aging, obesity, diabetes and metabolic syn - drome, cardiovascular disease, neurode - generative diseases, cancer, and chronic lung and kidney disease.

Fig. 2.

Deposition of IMAT and adipocyte accumulation in mouse models of acute and chronic muscle damage. (A) Three-dimensional rendering illustrating IMAT deposition and enhanced adipocyte accumulation in between regenerating myofibers (left panel), alongside a transverse section imaged via laser confocal microscopy displaying accumulated Perilipin⁺ adipocytes following glycerol-induced damage (right panel). (B) Confocal microscopy images demonstrating the abundance of Perilipin adipocytes within the muscle stroma of dystrophic mdx limb skeletal muscles.

Fig. 3.

Adipocyte cell formation and IMAT deposition in vivo from muscle-resident PDGFRα⁺ fibro-adipogenic progenitors. (A) Pdgfrα lineage tracing shows the complex cell structures and protrusions of muscle-resident FAPs and their close steady-state contact with healthy myofibers. (B) Lineage tracing reveals that IMAT-associated adipocytes (perilipin⁺) are derived from PDGFRα-expressing FAPs.

Fig. 4.

Formation of lipid droplet-rich adipocytes from fibro-adipogenic progenitors in cell culture. (A) Mouse muscle FAPs can be readily differentiated into functional adipocytes containing lipid droplets, as stained with Oil Red O. (B) PDGFRα lineage tracing shows that FAPs can generate adipocytes in culture with lipid droplets of different sizes and abundance. (C) Human muscle FAPs can also be differentiated into adipocytes that heavily accumulate lipid droplets. (D) Ventricle-resident fibroblasts can also generate perilipin⁺ adipocytes in vitro, although their adipogenic potential is known to be restrained in vivo.