Chronic rotator cuff tears are among the most prevalent and debilitating upper extremity injuries. A tear of the rotator cuff tendon from its insertion results in muscle atrophy, inflammation, and an accumulation of substantial amounts of inter- and intramyocellular fat, commonly referred to as fatty degeneration. Identifying therapies that can reduce fatty degeneration are likely to profoundly improve the treatment of patients with chronic rotator cuff tears. Our long term goal is to enhance the treatment of rotator cuff tears through the understanding of the mechanisms underlying fatty degeneration. The recovery of injured muscle requires several cell types. Muscle stem cells, or satellite cells, play a critical role in the repair and regeneration of new muscle fibers following injury. Macrophages are a class of immune cell that have dual functions in promoting and suppressing inflammation, and also play an important role in regulating satellite cell activity. Pro- inflammatory M1 macrophages enhance inflammation and switch to an anti-inflammatory M2 phenotype to support regeneration. We identified a population of lipid-laden macrophages, or fatty macrophages, that surround large lipid droplets following rotator cuff tear and persist much longer than M1 or M2 macrophages. Fatty macrophages display similar features to foam cells in atherosclerosis, which are macrophages that uptake lipid in vascular walls and lead to the deposition of lipid in growing plaques. The role of fatty macrophages in the ontogeny of fatty degeneration following rotator cuff tear is unknown. Furthermore, the impact of fatty macrophages in the modulation of satellite cell activity is not known. Additionally, fatty macrophages in torn rotator cuff muscles express high levels of FSP27, a protein that plays a central role in the formation of large lipid droplets. The sustained presence of large lipid droples in fatty macrophages could contribute to the production of pro-inflammatory eicosanoids, and promote muscle degradation. Inhibiting FSP27 following rotator cuff tear may reduce lipid droplet induced inflammation and muscle degradation. Characterizing the role of fatty macrophages in satellite cell biology and in the development of fatty degeneration is critical to the understanding of the cellular regulation of lipid deposition and chronic muscle dysfunction following rotator cuff tear. Our working hypothesis is that fatty macrophages function in a paracrine fashion to induce muscle fiber atrophy and large lipid droplet accumulation following rotator cuff tears. This hypothesis is rigorously tested in three Specific Aims that use a multi-disciplinary approach involving a combination of single muscle fiber contractility measurements, molecular biology and targeted adeno- associated viral knockdown of FSP27 in a rat model of massive rotator cuff tears. These studies will provide knowledge that will enhance our understanding of fatty degeneration, and identify therapeutic targets that could improve the treatment of chronic rotator cuff tears.