Animal model for chronic massive rotator cuff tear: behavioural and histologic analysis

Sevivas, Nuno; Serra, S.; Portugal, Raquel; Teixeira, Fábio G.; Carvalho, M. Alice; Silva, Nuno; Espregueira-Mendes, João; Sousa, Nuno; Salgado, António J.

doi:10.1007/s00167-014-3441-3

Cited by 19 publications

(35 citation statements)

References 49 publications

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“…However, they showed pathological responses strongly similar to those observed in previous animal studies on RCT, an inflammatory response in early stage and intramuscular fatty infiltration as well as upregulation of adipogenic and myogenic gene expression. 8,25,41 Therefore, the mouse RCT model can be considered an appropriate model to understand the many aspects of the rotator cuff response to injury including muscle fatty infiltration within a short experimental period as compared with other animal models such as rabbit, sheep, and primates.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Lee

Kim

et al. 2017

J cachexia sarcopenia muscle

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BackgroundFatty infiltration in skeletal muscle is directly linked to loss of muscle strength and is associated with various adverse physical outcomes such as muscle atrophy, inflammation, insulin resistance, mobility impairments, and even mortality in the elderly. Aging, mechanical unloading, muscle injury, and hormonal imbalance are main causes of muscle fat accumulation, and the fat cells are derived from muscle stem cells via adipogenic differentiation. However, the pathogenesis and molecular mechanisms of fatty infiltration in muscles are still not fully defined. Fatty acid‐binding protein 4 (FABP4) is a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism. Rotator cuff tear (RCT) usually occurs in the elderly and is closely related with fatty infiltration in injured muscle. To investigate potential mechanisms for fatty infiltration other than adipogenic differentiation of muscle stem cells, we examined the role of FABP4 in muscle fatty infiltration in an RCT mouse model.MethodsIn the RCT model, we evaluated the expression of FABP4 by qRT‐PCR, western blotting, and immunohistochemical analyses. Histological changes such as inflammation and fat accumulation in the injured muscles were examined immunohistochemically. To evaluate whether hypoxia induces FABP4 expression, the levels of FABP4 mRNA and protein in C3H10T1/2 cells after hypoxia were examined. Using a transient transfection assay in 293T cells, we assessed the promoter activity of FABP4 by hypoxia‐inducible factors (HIFs). Additionally, we evaluated the reduction in FABP4 expression and fat accumulation using specific inhibitors for HIF1 and FABP4, respectively.ResultsFABP4 expression was significantly increased after RCT in mice, and its expression was localized in the intramuscular fatty region. Rotator cuff tear‐induced FABP4 expression was up‐regulated by hypoxia. HIF1α, which is activated by hypoxia, augmented the promoter activity of FABP4, together with HIF1β. Hypoxia‐induced FABP4 expression was significantly decreased by HIF1 inhibitor treatment. Furthermore, in RCT model mice, fat accumulation was remarkably reduced by FABP4 inhibitor treatment.ConclusionsThis study shows that RCT induces FABP4 expression, leading to fat accumulation in injured muscle. FABP4 transcription is regulated by the direct binding of HIF1 to the FABP4 promoter in the hypoxic condition induced by RCT. Fat accumulation in injured muscle was reduced by the inhibition of FABP4. Ultimately, in the RCT model, we identified a novel mechanism for fatty infiltration by FABP4, which differs from adipogenic differentiation of muscle stem cells, and we found that fatty infiltration might be regulated by inhibition of HIF1 or FABP4.

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Section: Discussionmentioning

confidence: 99%

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Lee

Kim

et al. 2017

J cachexia sarcopenia muscle

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“…Therefore, the majority of studies for rotator cuff tendon tears employ an acute laceration injury of otherwise healthy tendon. These models include detachment of the supraspinatus tendon, either alone or in tandem with the infraspinatus or other tendons, to model massive rotator cuff tears . Reattachment surgeries are typically carried out immediately after detachment, and overall healing evaluated at later timepoints .…”

Section: Rotator Cuff Injury Modelsmentioning

confidence: 99%

“…Prolonged unloading resulted in tendon retraction, muscle atrophy, fatty infiltration, and fibrotic scarring. Despite eventual repair, these studies generally suggested that the pathological events associated with unloading cannot be reversed by simple reattachment …”

Section: Rotator Cuff Injury Modelsmentioning

confidence: 99%

“…These models include detachment of the supraspinatus tendon, either alone or in tandem with the infraspinatus or other tendons, to model massive rotator cuff tears. [18][19][20]33,34 Reattachment surgeries are typically carried out immediately after detachment, and overall healing evaluated at later timepoints. 21,22,[35][36][37][38][39][40][41] Because the laceration injuries and repairs are quite invasive, the environment after injury differs in significant ways from degenerationinduced tears observed in the clinic.…”

Section: Models Of Acute Injury and Repairmentioning

confidence: 99%

“…Despite eventual repair, these studies generally suggested that the pathological events associated with unloading cannot be reversed by simple reattachment. 18,20,33,34…”

Section: Models Of Acute Injury and Repairmentioning

confidence: 99%

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Biologics and stem cell‐based therapies for rotator cuff repair

Bianco

Moser

Galatz

et al. 2018

Annals of the New York Academy of Sciences

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The rotator cuff is composed of several distinct muscles and tendons that function in concert to coordinate shoulder motion. Injuries to these tendons frequently result in permanent dysfunction and persistent pain. Despite considerable advances in operation techniques, surgical repair alone still does not fully restore rotator cuff function. This review focuses on recent research in the use of biologics and stem cell-based therapies to augment repair, highlighting promising avenues for future work and remaining challenges. While a number of animal models are used for rotator cuff studies, the anatomy of the rotator cuff varies dramatically between species. Since the rodent rotator cuff shares the most anatomical features with the human, this review will focus primarily on rodent models to enable consistent interpretation of outcome measures.

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Rotator cuff muscle fibrosis can be assessed using ultrashort echo time magnetization transfer MRI with fat suppression

Chang,

Suprana,

Tang

et al. 2023

NMR in Biomedicine

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Muscle degeneration following rotator cuff tendon tearing is characterized by fatty infiltration and fibrosis. While tools exist for the characterization of fat, the ability to noninvasively assess muscle fibrosis is limited. The purpose of this study was to evaluate the capability of quantitative ultrashort echo time T1 (UTE‐T1) and UTE magnetization transfer (UTE‐MT) mapping with and without fat suppression (FS) for the differentiation of injured and control rotator cuff muscles and for the detection of fibrosis. A rat model of chronic massive rotator cuff tearing (n = 12) was used with tenotomy of the right supraspinatus and infraspinatus tendons and silicone implants to prevent healing. Imaging was performed on a 3‐T scanner, and UTE‐T1 mapping with and without FS and UTE‐MT with and without FS for macromolecular fraction (MMF) mapping was performed. At 20 weeks postinjury, T1 and MMF were measured in the supraspinatus and infraspinatus muscles of the injured and contralateral, internal control sides. Histology was performed and connective tissue fraction (CTF) was measured, defined as the area of collagen‐rich extracellular matrix divided by the total muscle area. Paired t‐tests and correlation analyses were performed. Significant differences between injured and control sides were found for CTF in the supraspinatus (mean ± SD, 14.5% ± 3.9% vs. 11.3% ± 3.7%, p = 0.01) and infraspinatus (17.0% ± 5.4% vs. 12.5% ± 4.6%, p < 0.01) muscles, as well as for MMF using UTE‐MT FS in the supraspinatus (9.7% ± 0.3% vs. 9.5% ± 0.2%, p = 0.04) and infraspinatus (10.9% ± 0.8% vs. 10.1% ± 0.5%, p < 0.01) muscles. No significant differences between sides were evident for T1 without or with FS or for MMF using UTE‐MT. Only MMF using UTE‐MT FS was significantly correlated with CTF for both supraspinatus (r = 0.46, p = 0.03) and infraspinatus (r = 0.51, p = 0.01) muscles. Fibrosis occurs in rotator cuff muscle degeneration, and the UTE‐MT FS technique may be helpful to evaluate the fibrosis component, independent from the fatty infiltration process.

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Animal model for chronic massive rotator cuff tear: behavioural and histologic analysis

Cited by 19 publications

References 49 publications

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Fatty acid‐binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia‐inducible factor 1 in mice

Biologics and stem cell‐based therapies for rotator cuff repair

Rotator cuff muscle fibrosis can be assessed using ultrashort echo time magnetization transfer MRI with fat suppression

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