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The purpose of this exploratory analysis was to compare the impact of movement pattern training (MoveTrain) and standard strength and flexibility training (Standard) on muscle volume, strength and fatty infiltration in patients with hip‐related groin pain (HRGP). We completed a secondary analysis of data collected during an assessor‐blinded randomized control trial. Data were used from 27 patients with HRGP, 15–40 years, who were randomized into MoveTrain or Standard groups. Both groups participated in their training protocol (MoveTrain, n = 14 or Standard, n = 13) which included 10 supervised sessions over 12 weeks and a daily home exercise program. Outcome measures were collected at baseline and immediately after treatment. Magnetic resonance images data were used to determine muscle fat index (MFI) and muscle volume. A hand‐held dynamometer was used to assess isometric hip abductor and extensor strength. The Standard group demonstrated a significant posttreatment increase in gluteus medius muscle volume compared to the MoveTrain group. Both groups demonstrated an increase in hip abductor strength and reduction in gluteus minimus and gluteus maximus MFI. The magnitude of change for all outcomes were modest. Statement of Clinical Significance: Movement pattern training or a program of strength/flexibility training may be effective at improving hipabductor strength and reducing fatty infiltration in the gluteal musculature among those with HRGP. Further research is needed to betterunderstand etiology of strength changes and impact of muscle volume and MFI in HRGP and the effect of exercise on muscle structure andfunction. [ABSTRACT FROM AUTHOR]

Muscle atrophy and fatty infiltration have been directly correlated with higher rates of incomplete or failed healing following surgical repair of the rotator cuff. The purpose of this study was to evaluate clinically relevant functional and morphological changes in the supraspinatus muscle at various time points in this model of rotator cuff tendinopathy. Subacromial impingement was induced in 47, male C57BL/6 mice (total 94 limbs) by implantation of a metal clip in the subacromial space. Specimens were evaluated at 4, 6, and 12 weeks postoperatively. Gait analysis was used to measure various kinematic parameters. Supraspinatus muscle wet weight, histology, and quantitative reverse‐transcription polymerase chain reaction analysis of genes related to muscle atrophy and adipogenesis were performed to characterize the structural, cellular, and molecular changes. Muscle atrophy and fatty infiltration was evident beginning at 6 weeks, with progression out to 12 weeks. Gait analysis identified significant functional changes in many aspects of gait and abnormal stance tracing as early as 4 weeks, verifying alterations in upper extremity function. We have demonstrated that clinically relevant changes to the supraspinatus muscle are seen starting 6 weeks after induction of subacromial impingement. Furthermore, the gait analysis provides key functional outcome measurements that may be useful for future evaluation of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Rotator cuff (RC) tears are a common cause of upper extremity disability. Any tear size can result in subsequent muscle atrophy and fatty infiltration (FI). Preoperative muscle degeneration can predict repair and postoperative functional outcomes. Muscle residential fibro‐adipogenic progenitors (FAPs) are found to be capable of differentiating into beige adipocytes that release factors to promote muscle growth. This study evaluated the regenerative potential of local cell transplantation of beige FAPs to mitigate muscle degeneration in a murine massive RC tear model. Beige FAPs were isolated from muscle in UCP‐1 reporter mice by flow cytometry as UCP‐1+/Sca1+/PDGFR+/CD31−/CD45−/integrin α7−. C57/BL6J mice undergoing supraspinatus tendon tear with suprascapular nerve transection (TT + DN) received either no additional treatment, phosphate‐buffered saline injection, or beige FAP injection 2 weeks after the initial injury. Forelimb gait analysis was used to assess shoulder function with DigiGait. Mice were sacrificed 6 weeks after cell transplantation. FI, fibrosis, fiber size, vascularity were analyzed and quantified via ImageJ. Our results showed that beige FAP transplantation significantly decreased fibrosis, FI, and atrophy, enhanced vascularization compared with saline injection and non‐treatment groups. Beige FAP transplantation also significantly improved shoulder function as measured by gait analysis. This study suggests that beige‐differentiated FAPs may serve as a treatment option for RC muscle atrophy and FI, thus improving shoulder function in patients with massive RC tendon tears. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1159‐1166, 2020 [ABSTRACT FROM AUTHOR]

Fatty infiltration (FI) of rotator cuff (RC) muscles is common in patients with RC tears. Studies have demonstrated that fibro‐adipogenic progenitors (FAPs), a population of resident muscle stem cells, are the main contributors of FI, which adversely affects muscle quality and RC repair success. Although FI is common in RC injuries, it is not frequently reported after other musculotendinous injuries. Additionally, studies have shown the development of different pathology patterns across muscle groups suggestive of intrinsic differences in cellular composition and behavior. This study evaluates FAP distribution and differentiation properties across anatomic locations in mice. Muscles from seven different anatomic locations were harvested from PDGFRα‐eGFP FAP reporter mice. FAPs were quantified using histology and FACS sorting with BD Aria II with CD31−/CD45−/Integrinα7−/Sca‐1+ and PDGFRα reporter signal (n = 3 per muscle). The cells were analyzed for adipogenesis using immunocytochemistry and for proliferation properties with Brdu‐Ki67 staining. In a separate group of mice, RC and tibialis anterior muscles received glycerol injection and were harvested after 2 weeks for FI quantification (n = 4). One‐way analysis of variance was used for statistical comparisons among groups, with significance at p < 0.05. FAPs from the RC, masseter, and paraspinal muscles were more numerous and demonstrated greater proliferative capacity and adipogenic potency than those from the tibialis anterior and gastrocnemius. The RC demonstrated significantly greater levels of FI than the tibialis anterior after glycerol‐injection injury. Clinical Significance: This study suggests differences in FAP distribution and differentiation characteristics may account for the propensity to develop FI in RC tears as compared with other musculotendinous injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1113‐1121, 2020 [ABSTRACT FROM AUTHOR]

ABSTRACT: Previous studies suggested that degradation of contractile tissue requires cleavage of the costamere, a structural protein complex that holds sarcomeres in place. This study examined if costamere turnover is affected by a rotator cuff tear in a previously established ovine model. We found the activity of focal adhesion kinase (FAK), a main regulator of costamere turnover, was unchanged at 2 weeks but decreased by 27% 16 weeks after surgical release of the infraspinatus tendon. This was accompanied by cleavage of the costamere protein talin into a 190 kDa fragment while full length talin remained unchanged. At 2 weeks after tendon release, muscle volume decreased by 17 cm3 from an initial 185 cm3, the fatty tissue volume was halved, and the contractile tissue volume remained unchanged. After 16 weeks, the muscle volume decreased by 36 cm3, contractile tissue was quantitatively lost, and the fat content increased by 184%. Nandrolone administration mitigated the loss of contractile tissue by 26% and prevented fat accumulation, alterations in FAK activity, and talin cleavage. Taken together, these findings imply that muscle remodeling after tendon release occurs in two stages. The early decrease of muscle volume is associated with reduction of fat; while, the second stage is characterized by substantial loss of contractile tissue accompanied by massive fat accumulation. Regulation of costamere turnover is associated with the loss of contractile tissue and seems to be impacted by nandrolone treatment. Clinically, the costamere may represent a potential intervention target to mitigate muscle loss after a rotator cuff tear. © 2017 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:272–281, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACT Histological and cell-level changes in the lumbar musculature in individuals with chronic lumbar spine degenerative conditions are not well characterized. Although prior literature supports evidence of changes in fiber type and size, little information exists describing the tissue quality and biology of pathological features of muscle in this population. The purpose of this study was to quantify multifidus tissue composition and structure, inflammation, vascularity, and degeneration in individuals with chronic degenerative lumbar spine pathology. Human multifidus biopsies were acquired from 22 consecutive patients undergoing surgery for chronic degenerative lumbar spine pathology. Relative fractions of muscle, adipose, and extracellular matrix were quantified along with muscle fiber type and cross-sectional area (CSA) and markers of inflammation, vascularity, satellite cell density, and muscle degeneration. On average, multifidus biopsies contained 48.5% muscle, 11.7% adipose tissue, and 26.1% collagen tissue. Elevated inflammatory cell counts (48.5 ± 30.0 macrophages/mm2) and decreased vascularity (275.6 ± 69.4 vessels/mm2) were also observed compared to normative values. Satellite cell densities were on average 13 ± 9 cells per every 100 muscle fibers. Large fiber CSA (3,996.0 ± 1,909.2 µm2) and a predominance of type I fibers (61.8 ± 18.0%) were observed in addition to evidence of pathological degeneration-regeneration cycling (18.8 ± 9.4% centrally nucleated fibers, and 55.2 ± 24.2% of muscle regions containing degeneration). High levels of muscle degeneration, inflammation, and decreased vascularity were commonly seen in human multifidus biopsies of individuals with lumbar spine pathology in comparison to normative data. Evidence of active muscle degeneration suggests that changes in muscle tissue are more complex than simple atrophy. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2700-2706, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Previous studies have suggested that macrophage-mediated chronic inflammation is involved in the development of rotator cuff muscle atrophy and degeneration following massive tendon tears. Increased RhoA signaling has been reported in chronic muscle degeneration, such as muscular dystrophy. However, the role of RhoA signaling in macrophage infiltration and rotator muscle degeneration remains unknown. Using a previously established rat model of massive rotator cuff tears, we found RhoA signaling is upregulated in rotator cuff muscle following a massive tendon-nerve injury. This increase in RhoA expression is greatly potentiated by the administration of a potent RhoA activator, lysophosphatidic acid (LPA), and is accompanied by increased TNFα and TGF-β1 expression in rotator cuff muscle. Boosting RhoA signaling with LPA significantly worsened rotator cuff muscle atrophy, fibrosis, and fatty infiltration, accompanied with massive monocytic infiltration of rotator cuff muscles. Co-staining of RhoA and the tissue macrophage marker CD68 showed that CD68+ tissue macrophages are the dominant cell source of increased RhoA signaling in rotator cuff muscles after tendon tears. Taken together, our findings suggest that LPA-mediated RhoA signaling in injured muscle worsens the outcomes of atrophy, fibrosis, and fatty infiltration by increasing macrophage infiltraion in rotator cuff muscle. Clinically, inhibiting RhoA signaling may represent a future direction for developing new treatments to improve muscle quality following massive rotator cuff tears. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1539-1547, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT Re-tear continues to be a problem after rotator cuff repair. Intramuscular botulinum toxin (Botox) injection can help optimize tension at the repair site to promote healing but could have an adverse effect on the degenerated muscle in a chronic tear. We hypothesized that Botox injection would improve repair characteristics without adverse effect on the muscle in a chronic rotator cuff tear model. The supraspinatus tendon of both shoulders in 14 rabbits underwent delayed repair 12 weeks after transection. One shoulder was treated with intramuscular Botox injection and the other with a saline control injection. Six weeks after repair, outcomes were based on biomechanics, histology, and magnetic resonance imaging. Botox-treated repairs were significantly weaker (2.64 N) than control repairs (5.51 N, p = 0.03). Eighty percent of Botox-treated repairs and 40% of control repairs healed with some partial defect. Fatty infiltration of the supraspinatus was present in all shoulders (Goutallier Grade 3 or 4) but was increased in the setting of Botox. This study provides additional support for the rabbit supraspinatus model of chronic cuff tear, showing consistent fatty infiltration. Contrary to our hypothesis, Botox had a negative effect on repair strength and might increase fatty infiltration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1152-1157, 2015. [ABSTRACT FROM AUTHOR]

ABSTRACT Rotator cuff tears (RCTs) are among the most common musculoskeletal injuries seen by orthopaedic surgeons. Clinically, massive cuff tears lead to unique pathophysiological changes in rotator cuff muscle, including atrophy, and massive fatty infiltration, which are rarely seen in other skeletal muscles. Studies in a rodent model for RCT have demonstrated that these histologic findings are accompanied by activation of the Akt/mammalian target of rapamycin (mTOR) and transforming growth factor-β (TGF-β) pathways following combined tendon-nerve injury. The purpose of this study was to compare the histologic and molecular features of rotator cuff muscle and gastrocnemius muscle-a major hindlimb muscle, following combined tendon-nerve injury. Six weeks after injury, the rat gastrocnemius did not exhibit notable fatty infiltration compared to the rotator cuff. Likewise, the adipogenic markers SREBP-1 and PPARγ as well as the TGF-β canonical pathway were upregulated in the rotator cuff, but not the gastrocnemius. Our study suggests that the rat rotator cuff and hindlimb muscles differ significantly in their response to a combined tendon-nerve injury. Clinically, these findings highlight the unique response of the rotator cuff to injury, and may begin to explain the poor outcomes of massive RCTs compared to other muscle-tendon injuries. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1046-1053, 2015. [ABSTRACT FROM AUTHOR]

ABSTRACT The hamstring tendon autograft is one of the most commonly used graft choices in Anterior cruciate ligament (ACL) reconstruction. There are conflicting results regarding postoperative hamstring strength deficits in patients who have had a hamstring graft. The semitendinosus tendon has been shown to regenerate after harvesting for ACL autograft, suggesting that the muscle has the potential to regain normal function. However, no studies have been performed to define the microstructural changes that occur in the semitendinosus muscle after tendon resection. In this study, we hypothesized that fatty infiltration of the semitendinosus muscle after tendon harvest in New Zealand White rabbits increases postoperatively and remains constant or increases during the first year of repair. The semitendinosus tendon was unilaterally detached and harvested from 15 rabbits. Five rabbits were sacrificed at 3-, 6-, and 12-month intervals, and the semitendinosus muscle-tendon units were analyzed. The contralateral unoperated limb served as the control. The gross tendon and muscle dimensions and histologic percentage of fatty infiltration were measured. We found no significant difference in fatty infiltration at any time point between the control muscle and test specimens and that there was no progression of fatty infiltration over time. If these results hold true in humans, natural repair of the hamstring muscle following tendon harvest during ACL autograft reconstruction is not inhibited by fatty infiltration. © 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1234-1239, 2013 [ABSTRACT FROM AUTHOR]

Rotator cuff tears (RCTs) are among the most common injuries seen in orthopedic patients. Chronic tears can result in the development of muscular atrophy and fatty infiltration. Despite the prevalence of RCTs, little is known about the underlying molecular pathways that produce these changes. Recently, we have shown that mammalian target of rapamycin (mTOR) signaling plays an important role in muscle atrophy that results from massive RCTs in a rat model. The purpose of this study was therefore to extend our understanding of mTOR signaling and evaluate its role in fatty infiltration after a combined tendon transection and suprascapular nerve denervation surgery. Akt/mTOR signaling was significantly increased and resulted in the up-regulation of two transcription factors: SREBP-1 and PPARγ. We also saw an increase in expression of adipogenic markers: C/EBP-α and FASN. Upon treatment with rapamycin, an inhibitor of mTOR, we observed a decrease in mTOR signaling, activity of transcription factors, and reduction in fatty infiltration. Therefore, our study suggests that mTOR signaling mediates rotator cuff fatty infiltration via SREBP-1 and PPARγ. Clinically, our finding may alter current treatment methods to address rotator cuff fatty infiltration. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 724-730, 2013 [ABSTRACT FROM AUTHOR]

Rotator cuff pathology is the most common shoulder problem seen by orthopedic surgeons. Rotator cuff muscle fatty infiltration and muscle atrophy are common in larger tears and are considered predicting factors for the prognosis of cuff repair. Clinically, MRI is the gold standard in determining fatty infiltration and muscle atrophy; however, analysis for MRI imaging is primarily qualitative in nature with the results lacking further validation. We have recently developed a mouse model of rotator cuff tears. The goal of this study is to quantify and verify rotator cuff muscle atrophy and fatty infiltration using high-resolution MRI in our mouse model. The rotator cuff muscles were analyzed for fat using a triglyceride quantification assay (TQA), muscle volume was measured through water displacement (WD), and histology. The study revealed that MRI had a high correlation with fat as measured with histology and TQA ( R2 = 098). MRI also correlated well with atrophy measured with WD and wet weight. This suggests that MRI is a reliable modality in evaluating the progression of fatty infiltration and muscle atrophy following rotator cuff tears in a small animal model. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 421-426, 2013 [ABSTRACT FROM AUTHOR]

Rotator cuff tears are a major cause of morbidity. Following rotator cuff tears, muscle atrophy and fatty infiltration begin in the tissue, limiting repair potential and leading to a higher re-tear rate and a worse functional outcome. We evaluated whether fatty degeneration resulting from a complete supraspinatus tear with retraction is associated with an injury to the suprascapular nerve. Four skeletally mature New Zealand white rabbits were randomized to receive an index procedure on either their right or left shoulder with the opposite shoulder serving as a control. At the index procedure, the supraspinatus tendon was transected at its insertion and allowed to retract. At 3 months, the rabbits were euthanized, and both supraspinatus muscles were harvested. The specimens were then examined with confocal microscopy and histology. Atrophy was grossly visible in all four test muscles, and fatty infiltration was confirmed with osmium tetroxide staining. In all four rabbits, the degree of denervation ( p = 0.71) and partial denervation ( p = 0.91) was not significantly different between control and experimental muscle. Rotator cuff tear does not affect the motor endplate or innervation status of the supraspinatus. Fatty infiltration occurs independent of denervation of the supraspinatus. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:99-104, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Muscle atrophy is a known consequence of muscle disuse, muscle denervation and tendon tear. Whereas after nerve injury muscle atrophies in the denervated area, the distribution of muscle atrophy following tear of its tendon is not known. Standardized MRI scans of 64 consecutive, painful shoulders were evaluated for supraspinatus tendon tearing, myotendinous retraction, supraspinatus muscle atrophy, fatty infiltration, ratio of the scapular (deep) and fascial (superficial) muscle area (“symmetry”) and position of the central tendon within the supraspinatus fossa. There were thirteen shoulders with no and eleven shoulders with partial thickness supraspinatus tendon tears. In the forty cases with full thickness tendon tear, there was significant muscle atrophy and fatty infiltration. Atrophy of the fascial muscle portion was 43%, on the bony side it was 9% (p &#60;0.005). The position of the central tendon within the supraspinatus fossa, was unaltered. Muscular changes following tendon tear occur highly asymmetrically: The muscle portion originating from the fascia primarily atrophies, the portion originating from the scapula primarily undergoes fatty infiltration. Muscular changes are not simply a consequence of muscle disuse, but dependent on architectural changes in the muscle. [Copyright &y& Elsevier]