Background The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration. Hypothesis After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers. Study Design Controlled laboratory study. Methods Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses. Results Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibro-cartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51 % increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%. Conclusion The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development of a stable bone-tendon interface, although decreases in muscle fiber specific force production were observed, and force production in fact declined. Clinical Relevance This study demonstrates that the inhibition of 5-LOX, COX-1, and COX-2 modulates the healing process of repaired rotator cuff tendons. Although further studies are necessary, the treatment of patients with licofelone after cuff repair may improve the development of a stable enthesis and enhance postoperative outcomes.

Background Following ACL reconstruction, there is significant atrophy of quadriceps muscles which can limit full recovery and place athletes at risk for recurrent injury with return to play. The etiology of this muscle atrophy is not fully understood. Hypothesis We hypothesized that circulating levels of pro-atrophy, pro-inflammatory and cartilage turnover cytokines and biomarkers would increase following ACL reconstruction. Study Design Descriptive laboratory study. Methods Subjects (N=18, mean age 28±2.4 years) underwent surgical reconstruction of the ACL following non-contact athletic injury. Circulating levels of biomarkers were measured along with SF-12, IKDC and objective knee strength measures preoperatively, and at 6 postoperative visits. Differences were tested using repeated measures one-way ANOVA tests. Results Myostatin, TGF-β and CRP levels were significantly increased in the early postoperative period, and returned to baseline. COMP levels decreased immediately after surgery and then returned to baseline. CCL2, CCL3, CCL4, CCL5, EGF, FGF-2, IGF-1, IL-10, IL-1α, IL-1β, IL-1ra, IL-6, myoglobin and TNF-α were not different over the course of the study. Conclusions An increase in potent atrophy-inducing cytokines and corresponding changes in knee strength and functional scores were observed following ACL reconstruction. Clinical Relevance Although further studies are necessary, the therapeutic inhibition of myostatin may help prevent the muscle atrophy that occurs following ACL reconstruction and provide an accelerated return of patients to sport.

No abstract

Background Chronic rotator cuff tears are a common source of shoulder pain and disability, and patients with chronic cuff tears often have substantial weakness, fibrosis, inflammation and fat accumulation. Identifying therapies to prevent the development of these pathologies will likely have a positive impact on clinical outcomes. Simvastatin is a drug with demonstrated anti-inflammatory and anti-fibrotic effects in many tissues, but had not previously been studied in the context of rotator cuff tears. We hypothesized that following the induction of a massive supraspinatus tear, simvastatin would protect muscles from a loss of force production and fibrosis. Methods We measured changes in muscle fiber contractility, histology and biochemical markers of fibrosis and fatty infiltration in rats that received a full-thickness supraspinatus tear and were treated with either carrier alone or simvastatin. Results Compared to vehicle treated controls, simvastatin did not have an appreciable effect on muscle fiber size, but treatment did increase muscle fiber specific force by 20%. Simvastatin also reduced collagen accumulation by 50%, but did not effect triglyceride content of muscles. Several favorable changes in the expression of genes and other markers of inflammation, fibrosis and regeneration were also observed. Conclusions Simvastatin partially protected muscles from the weakness that occurs as a result of chronic rotator cuff tear. Fibrosis was also markedly reduced in simvastatin treated animals. While further studies are necessary, statin medication could potentially help to improve outcomes for patients with rotator cuff tears.

Objectives Rotator cuff tears are among the most common and debilitating upper extremity injuries. Chronic cuff tears result in atrophy and an infiltration of fat into the muscle, a condition commonly referred to as ‘fatty degeneration’. While stem cell therapies hold promise for the treatment of cuff tears, a suitable immunodeficient animal model that could be used to study human or other xenograft-based therapies for the treatment of rotator cuff injuries had not previously been identified.Methods A full-thickness, massive supraspinatus and infraspinatus tear was induced in adult T-cell deficient rats. We hypothesised that, compared with controls, 28 days after inducing a tear we would observe a decrease in muscle force production, an accumulation of type IIB fibres, and an upregulation in the expression of genes involved with muscle atrophy, fibrosis and inflammation.Results Chronic cuff tears in nude rats resulted in a 30% to 40% decrease in muscle mass, a 23% reduction in production of muscle force, and an induction of genes that regulate atrophy, fibrosis, lipid accumulation, inflammation and macrophage recruitment. Marked large lipid droplet accumulation was also present.Conclusions The extent of degenerative changes in nude rats was similar to what was observed in T-cell competent rats. T cells may not play an important role in regulating muscle degeneration following chronic muscle unloading. The general similarities between nude and T-cell competent rats suggest the nude rat is likely an appropriate preclinical model for the study of xenografts that have the potential to enhance the treatment of chronically torn rotator cuff muscles.Cite this article: Bone Joint Res 2014;3:262–72.

Objectives:A common pathophysiological change that occurs in torn rotator cuff muscles is atrophy of muscle fibers and an accumulation of intramuscular fat, collectively referred to as "fatty degeneration." For many patients with chronic rotator cuff tears that undergo surgical repair, fatty degeneration is not resolved. The etiology of fatty degeneration has not been characterized in humans, and gaining greater insight into the mechanisms that lead to the development of atrophy and fat accumulation will likely improve the recovery of patients who undergo surgical repair of a torn rotator cuff. The purpose of this study was to gain a greater understanding of the changes in muscle fiber contractility, myofibril architecture and fat accumulation in patients with rotator cuff tears. We hypothesized that torn rotator cuff muscles have reduced muscle fiber force production, disordered myofibrils and an accumulation of fat vacuoles and lysosomes.Methods:This study was approved by our institution's IRB. Prior to enrollment in the study, informed consent was obtained from patients with a full thickness supraspinatus tear as verified by MRI or ultrasound by a fellowship-trained musculoskeletal radiologist. Biopsies of the supraspinatus and anterior deltoid were obtained at the time of repair and prepared for muscle contractility testing or microscopy. The contractility of permeabilized muscle fibers was performed as previously described, and force values of torn supraspinatus and intact deltoid muscles were compared to age-matched force values of healthy fibers sampled from the vastus lateralis muscle in a previous study. Scanning electron micrographs and immunohistochemistry were also performed on select muscle biopsies.Results:Compared with healthy muscle fibers from the vastus lateralis, there was a 29% reduction in specific force (maximum isometric force normalized to fiber cross-sectional area) in torn supraspinatus muscles, and a 34% reduction in specific force for deltoid muscle fibers (Figure 1A, P<0.05). Numerous large intramuscular lipid vacuoles and lysosomes were observed in areas of myofibril degradation (Figure 1B) and streaming of force transmitting Z-disks was often present (Figure 1C). Fatty macrophages, also known as foam cells, were also observed in the ECM between muscle fibers in electron micrographs (Figure 1D) and using a macrophage/foam cell surface marker and BODIPY fluorescent lipid stain (Figure 1E).Conclusion:Combined, these results identify chronic structural and mechanical changes in torn rotator cuff muscles that may explain the poor functional capacity of the muscles after repair. While the supraspinatus muscle had reduced force production, a reduction in force was also noted in the deltoid which may parallel symptomatic rotator cuff disease. Further, the accumulation of fat in large lipid vacuoles and high lysosome densities near myofibrils suggest that a portion of the intramyocellular fat that accumulates in torn cuff muscles likely comes as a result of myofibril degradation. We have als...