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Inhibition of calpain delays early muscle atrophy after rotator cuff tendon release in sheep.

ABSTRACT: Chronic rotator cuff (RC) tears are characterized by retraction, fat accumulation, and atrophy of the affected muscle. These features pose an intractable problem for surgical repair and subsequent recovery, and their prevention may be easier than reversal. Using an established ovine model, we tested the hypothesis that inhibition of the protease calpain mitigates m. infraspinatus atrophy by preservation of the myofibers' structural anchors in the sarcolemma (the costameres). Already 2 weeks of distal tendon release led to a reduction in muscle volume (-11.6 ± 9.1 cm³ , P = 0.038) and a 8.3% slow-to-fast shift of the fiber area (P = 0.046), which were both entirely abolished by chronic local administration of the calpain inhibitor calpeptin alone, and in combination with sildenafil. Calpain inhibition blunted the retraction of the muscle-tendon unit by 0.8-1.0 cm (P = 0.020) compared with the control group, and prevented cleavage of the costameric protein talin. Calpain 1 and 2 protein levels increased in the medicated groups after 4 weeks, counteracting the efficacy of calpeptin. Hence atrophic changes emerged after 4 weeks despite ongoing treatment. These findings suggest that the early muscular adaptations in the specific case of RC tear in the ovine model are indistinguishable from the atrophy and slow-to-fast fiber transformation observed with conventional unloading and can be prevented for 2 weeks. Concluding, calpain is a potential target to extend the temporal window for reconstruction of the ruptured RC tendon before recovery turns impossible.

SUBMITTER: Ruoss S

PROVIDER: S-EPMC6215759 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Inhibition of calpain delays early muscle atrophy after rotator cuff tendon release in sheep.

Ruoss Severin S Kindt Philipp P Oberholzer Linus L Rohner Marco M Jungck Ladina L Abdel-Aziz Sara S Fitze Daniel D Rosskopf Andrea B AB Klein Karina K von Rechenberg Brigitte B Gerber Christian C Wieser Karl K Flück Martin M

Physiological reports 20181101 21

Chronic rotator cuff (RC) tears are characterized by retraction, fat accumulation, and atrophy of the affected muscle. These features pose an intractable problem for surgical repair and subsequent recovery, and their prevention may be easier than reversal. Using an established ovine model, we tested the hypothesis that inhibition of the protease calpain mitigates m. infraspinatus atrophy by preservation of the myofibers' structural anchors in the sarcolemma (the costameres). Already 2 weeks of d ...[more]

PMID: 30393967

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Project description:The rotator cuff consists of several tendons and muscles that provide stability and force transmission in the shoulder joint. Whereas most rotator cuff tears are amenable to suture repair, the overall success rate of repair is low, and massive tears are prone to re-tear. Extracellular matrix (ECM) patches are used to augment suture repair, but they have limitations. Tissue-engineered approaches provide a promising solution for massive rotator cuff tears. Previous studies have shown that, compared to nonaligned scaffolds, aligned electrospun polymer scaffolds exhibit greater anisotropy and exert a greater tenogenic effect. Nevertheless, achieving rapid cell infiltration through the full thickness of the scaffold is challenging, and scaling to a translationally relevant size may be difficult. Our goal was to evaluate whether a novel method of alignment, combining a multilayered electrospinning technique with a hybrid of several electrospinning alignment techniques, would permit cell infiltration and collagen deposition through the thickness of poly(ε-caprolactone) scaffolds following seeding with human adipose-derived stem cells. Furthermore, we evaluated whether multilayered aligned scaffolds enhanced collagen alignment, tendon-related gene expression, and mechanical properties compared to multilayered nonaligned scaffolds. Both aligned and nonaligned multilayered scaffolds demonstrated cell infiltration and ECM deposition through the full thickness of the scaffold after only 28days of culture. Aligned scaffolds displayed significantly increased expression of tenomodulin compared to nonaligned scaffolds and exhibited aligned collagen fibrils throughout the full thickness, the presence of which may account for the increased yield stress and Young's modulus of cell-seeded aligned scaffolds along the axis of fiber alignment.Statement of significanceRotator cuff tears are an important clinical problem in the shoulder, with over 300,000 surgical repairs performed annually. Re-tear rates may be high, and current methods used to augment surgical repair have limited evidence to support their clinical use due to inadequate initial mechanical properties and slow cellular infiltration. Tissue engineering approaches such as electrospinning have shown similar challenges in previous studies. In this study, a novel technique to align electrospun fibers while using a multilayered approach demonstrated increased mechanical properties and development of aligned collagen through the full thickness of the scaffolds compared to nonaligned multilayered scaffolds, and both types of scaffolds demonstrated rapid cell infiltration through the full thickness of the scaffold.

Project description:BackgroundThe 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.HypothesisAfter 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 designControlled laboratory study.MethodsRats 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.ResultsCompared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibrocartilage 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%.ConclusionThe 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 relevanceThis 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.

Project description:BackgroundThe injection of mesenchymal stem cells (MSCs) mitigates fat accumulation in released rotator cuff muscle after tendon repair in rodents.PurposeTo investigate whether the injection of autologous MSCs halts muscle-to-fat conversion after tendon repair in a large animal model for rotator cuff tendon release via regional effects on extracellular fat tissue and muscle fiber regeneration.Study designControlled laboratory study.MethodsInfraspinatus (ISP) muscles of the right shoulder of Swiss Alpine sheep (n = 14) were released by osteotomy and reattached 16 weeks later without (group T; n = 6) or with (group T-MSC; n = 8) electropulse-assisted injection of 0.9 Mio fluorescently labeled MSCs as microtissues with media in demarcated regions; animals were allowed 6 weeks of recovery. ISP volume and composition were documented with computed tomography and magnetic resonance imaging. Area percentages of muscle fiber types, fat, extracellular ground substance, and fluorescence-positive tissue; mean cross-sectional area (MCSA) of muscle fibers; and expression of myogenic (myogenin), regeneration (tenascin-C), and adipogenic markers (peroxisome proliferator-activated receptor gamma [PPARG2]) were quantified in injected and noninjected regions after recovery.ResultsAt 16 weeks after tendon release, the ISP volume was reduced and the fat fraction of ISP muscle was increased in group T (137 vs 185 mL; 49% vs 7%) and group T-MSC (130 vs 166 mL; 53% vs 10%). In group T-MSC versus group T, changes during recovery after tendon reattachment were abrogated for fat-free mass (-5% vs -29%, respectively; P = .018) and fat fraction (+1% vs +24%, respectively; P = .009%). The area percentage of fat was lower (9% vs 20%; P = .018) and the percentage of the extracellular ground substance was higher (26% vs 20%; P = .007) in the noninjected ISP region for group T-MSC versus group T, respectively. Regionally, MCS injection increased tenascin-C levels (+59%) and the water fraction, maintaining the reduced PPARG2 levels but not the 29% increased fiber MCSA, with media injection.ConclusionIn a sheep model, injection of autologous MSCs in degenerated rotator cuff muscle halted muscle-to-fat conversion during recovery from tendon repair by preserving fat-free mass in association with extracellular reactions and stopping adjuvant-induced muscle fiber hypertrophy.Clinical relevanceA relatively small dose of MSCs is therapeutically effective to halt fatty atrophy in a large animal model.

Project description:OBJECTIVES:Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1?) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1? is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1? following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. METHODS:Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. RESULTS:At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. CONCLUSIONS:GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred.Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57-65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1.

Project description:BACKGROUND:Rotator cuff (RC) tears are common tendon injuries seen in orthopaedic patients. Successful repair of large and massive RC tears remains a challenge due to our limited understanding of the pathophysiological features of this injury. Clinically relevant small animal models that can be used to study the pathophysiological response to repair are limited by the lack of chronic repair models. PURPOSE:To develop a highly clinically relevant mouse model of delayed RC repair. STUDY DESIGN:Controlled laboratory study. METHODS:Three-month-old C57BL/6J mice underwent unilateral supraspinatus (SS) and infraspinatus (IS) tendon tear with immediate, 2-week delayed, or 6-week delayed tendon repair. Animals with no repair or sham surgery served as controls. Gait analysis was conducted to measure shoulder function at 2 weeks and 6 weeks after surgery. Animals were sacrificed 6 weeks after the last surgery. Shoulder joint, SS, and IS muscles were harvested and analyzed histologically. Ex vivo mechanical testing of intact and repaired SS and IS tendons was conducted. Reverse-transcriptase polymerase chain reaction was performed on SS and IS muscles to quantify atrophy, fibrosis, and fatty infiltration-related gene expression. RESULTS:Histological and tendon mechanical testing showed that torn tendons could be successfully repaired as late as 6 weeks after transection. However, significant atrophy and fatty infiltration of muscle, with impaired shoulder function, were persistent in the 6-week delayed repair group. Shoulder function correlated with the severity of RC muscle weight loss and fatty infiltration. CONCLUSION:We successfully developed a clinically relevant mouse model of delayed RC repair. Six-week delayed RC repair resulted in persistent muscle atrophy and fatty infiltration with inferior shoulder function compared with acute repair. CLINICAL RELEVANCE:Our novel mouse model could serve as a powerful tool to understand the pathophysiological and cellular/molecular mechanisms of RC muscle and tendon degeneration, eventually improving our strategies for treating and repairing RC tears.

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Inhibition of calpain delays early muscle atrophy after rotator cuff tendon release in sheep.

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Inhibition of calpain delays early muscle atrophy after rotator cuff tendon release in sheep.

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