It is well known that the formation of fat deposits within muscle tissue is a feature of aging, and is also associated with a variety of muscle disorders. Here, researchers explore how exactly this infiltration of fat into muscle harms muscle function, with a focus on regenerative capacity. At present physical activity is the most reliable approach to prevent or reduce fat infiltration of muscle tissue, but it seems likely that at least some of the growing number of weight loss drugs in development, many of which improve upon GLP-1 receptor agonists by neither reducing calorie intake nor causing loss of muscle mass, will also be effective.
Adipose tissue acts as an energy storage as well as an endocrine organ. However, different fat depots, such as subcutaneous (SAT), visceral (VAT), and intramuscular adipose tissue (IMAT), have stark metabolic and phenotypic differences. IMAT, the accumulation of adipocytes between individual myofibers within skeletal muscle, is a pathological hallmark of muscular dystrophies, but it is also present in a spectrum of metabolic disorders, including diabetes, obesity, and sarcopenia. The progressive infiltration of IMAT within muscle tissue has been closely associated with loss of muscle mass, metabolic dysfunction, disease progression, and impairment of patient mobility.
The cellular origin of IMAT is a population of stem cells located in the muscle interstitium, called fibro-adipogenic progenitors (FAPs). In a healthy muscle, FAPs are critical in maintaining muscle mass during homeostasis and playing a central role in muscle regeneration. FAPs secrete pro-myogenic factors to aid the cellular origin of muscle fibers, muscle stem cells (MuSCs), in their differentiation process toward myofibers. With age and disease, however, FAPs can also differentiate into either adipocytes, leading to IMAT formation or myofibroblasts, giving rise to fibrosis.
To understand the influence of IMAT on skeletal muscle, we created a conditional mouse model, termed mFATBLOCK that blocked IMAT formation by deleting peroxisome proliferator-activated receptor gamma (Pparγ) from FAPs. This deletion had no effect under normal conditions but successfully prevented IMAT accumulation after an adipogenic injury. Mechanistically, our data argues that IMAT acts as a physical barrier and prevents new nascent myofiber formation during early regeneration, as well as myofiber hypertrophy during the later regenerative phase. Consequently, this results in a functionally weakened muscle that has both fewer and smaller myofibers.
Link: https://doi.org/10.1016/j.celrep.2025.116021
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