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.

Public Health Relevance

to public health is based upon the tremendous impact that rotator cuff injuries have on the quality of life. There is a substantial lack in our understanding of the cellular and molecular pathogenesis of rotator cuff fatty degeneration. Increasing our understanding of fundamental mechanisms of rotator cuff degeneration and regeneration is highly relevant to the NIH's mission to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AR065931-01A1
Application #
8719516
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tyree, Bernadette
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gumucio, Jonathan P; Flood, Michael D; Roche, Stuart M et al. (2016) Stromal vascular stem cell treatment decreases muscle fibrosis following chronic rotator cuff tear. Int Orthop 40:759-64
Mendias, Christopher L; Schwartz, Andrew J; Grekin, Jeremy A et al. (2016) Changes in muscle fiber contractility and extracellular matrix production during skeletal muscle hypertrophy. J Appl Physiol (1985) :jap.00719.2016
Wilde, Jeffrey M; Gumucio, Jonathan P; Grekin, Jeremy A et al. (2016) Inhibition of p38 mitogen-activated protein kinase signaling reduces fibrosis and lipid accumulation after rotator cuff repair. J Shoulder Elbow Surg 25:1501-8
Hudgens, Joshua L; Sugg, Kristoffer B; Grekin, Jeremy A et al. (2016) Platelet-Rich Plasma Activates Proinflammatory Signaling Pathways and Induces Oxidative Stress in Tendon Fibroblasts. Am J Sports Med 44:1931-40
Davis, Max E; Korn, Michael A; Gumucio, Jonathan P et al. (2015) Simvastatin reduces fibrosis and protects against muscle weakness after massive rotator cuff tear. J Shoulder Elbow Surg 24:280-7
Roche, Stuart M; Gumucio, Jonathan P; Brooks, Susan V et al. (2015) Measurement of Maximum Isometric Force Generated by Permeabilized Skeletal Muscle Fibers. J Vis Exp :e52695
Schwartz, Andrew J; Sarver, Dylan C; Sugg, Kristoffer B et al. (2015) p38 MAPK signaling in postnatal tendon growth and remodeling. PLoS One 10:e0120044
Mendias, Christopher L; Lynch, Evan B; Gumucio, Jonathan P et al. (2015) Changes in skeletal muscle and tendon structure and function following genetic inactivation of myostatin in rats. J Physiol 593:2037-52
Gumucio, Jonathan P; Sugg, Kristoffer B; Mendias, Christopher L (2015) TGF-β superfamily signaling in muscle and tendon adaptation to resistance exercise. Exerc Sport Sci Rev 43:93-9
Mendias, Christopher L; Bakhurin, Konstantin I; Gumucio, Jonathan P et al. (2015) Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice. Aging Cell 14:704-6

Showing the most recent 10 out of 13 publications