TGF-β Small Molecule Inhibitor SB431542 Reduces Rotator Cuff Muscle Fibrosis and Fatty Infiltration By Promoting Fibro/Adipogenic Progenitor Apoptosis

Abstract

Rotator cuff tears represent a large burden of muscle-tendon injuries in our aging population. While small tears can be repaired surgically with good outcomes, critical size tears are marked by muscle atrophy, fibrosis, and fatty infiltration, which can lead to failed repair, frequent re-injury, and chronic disability. Previous animal studies have indicated that Transforming Growth Factor-β (TGF-β) signaling may play an important role in the development of these muscle pathologies after injury. Here, we demonstrated that inhibition of TGF-β1 signaling with the small molecule inhibitor SB431542 in a mouse model of massive rotator cuff tear results in decreased fibrosis, fatty infiltration, and muscle weight loss. These observed phenotypic changes were accompanied by decreased fibrotic, adipogenic, and atrophy-related gene expression in the injured muscle of mice treated with SB431542. We further demonstrated that treatment with SB431542 reduces the number of fibro/adipogenic progenitor (FAP) cells—an important cellular origin of rotator cuff muscle fibrosis and fatty infiltration, in injured muscle by promoting apoptosis of FAPs. Together, these data indicate that the TGF-β pathway is a critical regulator of the degenerative muscle changes seen after massive rotator cuff tears. TGF-β promotes rotator cuff muscle fibrosis and fatty infiltration by preventing FAP apoptosis. TGF-β regulated FAP apoptosis may serve as an important target pathway in the future development of novel therapeutics to improve muscle outcomes following rotator cuff tear.

Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren’s syndrome

“…Fatty infiltration and fatty replacement are terms that describe processes by which tissue, generally exocrine tissue, is replaced in whole or in part by adipocytes [33, 34, 35]. Fatty infiltration of tissue is a normal part of the aging process, though pathological and accelerated forms can occur after tissue injury [36, 37]. Thymic involution, for example, is a systematic replacement of thymic tissue with adipocytes which occurs as an organism ages [38].…”

Quantitative Analysis of Immune Cell Subset Infiltration of Supraspinatus Muscle After Severe Rotator Cuff Injury

“…Clinical studies contradict each other as to whether RCT-induced suprascapular neuropathy contributes to muscle degeneration [57], [61]. Nevertheless, in pre-clinical models, suprascapular denervation helps recapitulate the degree of muscle degeneration observed in human cases of RCT[30], [31], [62]. In the present study, TT+DN increases MP, MO, and DC counts by at least 2-fold (Fig 1) and slightly increases CD206 + enrichment of the MΦ pool compared to TT (Fig 2).…”

The role of mechanobiology in progression of rotator cuff muscle atrophy and degeneration

“…Further complicating the evaluation of SCs in the context of RC disease are other potential environmental contributors to SC dysfunction known to occur in the torn RC. The torn RC environment demonstrates altered expression of soluble factors as well as increased inflammation and oxidative stress, which are all potent mediators of SC function that may be exacerbated by muscle injury. Pro‐inflammatory signaling and oxidative stress stimulate SC proliferation, but blocks differentiation, and self‐renewal via the TNF/TWEAK/NF‐κB and Notch signaling axes, while anti‐inflammatory signals aid in differentiation (Fig.…”