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Reduced Myogenic and Increased Adipogenic Differentiation Capacity of Rotator Cuff Muscle Stem Cells

Schubert, Manuel F., MD, MS1; Noah, Andrew C., MS1; Bedi, Asheesh, MD1; Gumucio, Jonathan P., PhD1; Mendias, Christopher L., PhD, ATC1,2,3

doi: 10.2106/JBJS.18.00509
Scientific Articles
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Background: Fat accumulation commonly occurs in chronically torn rotator cuff muscles, and increased fat within the rotator cuff is correlated with poor clinical outcomes. The extent of lipid deposition is particularly pronounced in injured rotator cuff muscles compared with other commonly injured muscles such as the gastrocnemius. Satellite cells, which are a tissue-resident muscle stem-cell population, can differentiate into fat cells. We hypothesized that satellite cells from the rotator cuff have greater intrinsic adipogenic differentiation potential than do gastrocnemius satellite cells, and this difference is due to variations in epigenetic imprinting between the cells.

Methods: Satellite cells from gastrocnemius and rotator cuff muscles of mice were cultured in adipogenic media, and the capacity to differentiate into mature muscle cells and adipogenic cells was assessed (n ≥ 9 plates per muscle group). We also performed DNA methylation analysis of gastrocnemius and rotator cuff satellite cells to determine whether epigenetic differences were present between the 2 groups (n = 5 mice per group).

Results: Compared with the gastrocnemius, satellite cells from the rotator cuff had a 23% reduction in myogenic differentiation and an 87% decrease in the expression of the differentiated muscle cell marker MRF4 (myogenic regulatory factor 4). With respect to adipogenesis, rotator cuff satellite cells had a 4.3-fold increase in adipogenesis, a 12-fold increase in the adipogenic transcription factor PPARγ (peroxisome proliferator-activated receptor gamma), and a 65-fold increase in the adipogenic marker FABP4 (fatty-acid binding protein 4). Epigenetic analysis identified 355 differentially methylated regions of DNA between rotator cuff and gastrocnemius satellite cells, and pathway enrichment analysis suggested that these regions were involved with lipid metabolism and adipogenesis.

Conclusions: Satellite cells from rotator cuff muscles have reduced myogenic and increased adipogenic differentiation potential compared with gastrocnemius muscles. There appears to be a cellular and genetic basis behind the generally poor rates of rotator cuff muscle healing.

Clinical Relevance: The reduced myogenic and increased adipogenic capacity of rotator cuff satellite cells is consistent with the increased fat content and poor muscle healing rates often observed for chronically torn rotator cuff muscles. For patients undergoing rotator cuff repair, transplantation of autologous satellite cells from other muscles less prone to fatty infiltration may improve clinical outcomes.

1Departments of Orthopaedic Surgery (M.F.S., A.C.N., A.B, J.P.G, and C.L.M.) and Molecular and Integrative Physiology (A.C.N, J.P.G., and C.L.M.), University of Michigan Medical School, Ann Arbor, Michigan

2Hospital for Special Surgery, New York, NY

3Departments of Physiology and Biophysics and Orthopaedic Surgery, Weill Cornell Medical College, New York, NY

E-mail address for C.L. Mendias: MendiasC@hss.edu

Investigation performed at the University of Michigan Medical School, Ann Arbor, Michigan

Disclosure: Funding support for this study was provided by the Orthopaedic Research and Education Foundation and NIH grant F31-AR065931. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had other relationships or activities that could be perceived to influence, or have the potential to influence, what was written in this work (http://links.lww.com/JBJS/F34).

Copyright © 2019 by The Journal of Bone and Joint Surgery, Incorporated
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