A Mouse Model of Massive Rotator Cuff Tears

Liu, Xuhui; Laron, Dominique; Natsuhara, Kyle M.; Manzano, Givenchy; Kim, Hubert T.; Feeley, Brian T.

doi:10.2106/jbjs.k.00620

Cited by 97 publications

(130 citation statements)

References 30 publications

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“…Rotator cuff tear is a representative musculoskeletal disorder leading to fatty infiltration in aged individuals. In this study, we utilized a mouse RCT model to investigate the role of FABP4 in muscle fatty infiltration because a previous study demonstrated that a mouse model of RCT shows similar pathological changes, including muscle atrophy and fatty infiltration seen in patients 9. Interestingly, mice showed a surprisingly fast wound healing after surgery.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, RCT could be considered a good model to understand age‐associated muscle fatty infiltration. To date, the mechanism of muscle fatty infiltration in RCT has been investigated using various animal models 8, 9, 10, 11, 12, 13. However, the molecular mechanisms underlying rotator cuff muscle atrophy and fatty infiltration remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…Rowshan et al 34 examined a rabbit subscapularis tenotomised model and concluded that fatty infiltration of the muscle occurs with chronic rotator cuff tears and may be explained by nerve injury. Liu et al 35 demonstrated that significant and consistent muscle atrophy and fatty infiltration were observed in the rotator cuff muscles after rotator cuff tendon transection. They found that denervation significantly increases the amount of muscle atrophy and fatty infiltration after a rotator cuff tear.…”

Section: All Authors Contributed To the Conception Design And Prepamentioning

confidence: 98%

“…Other researchers proposed that severe fatty degeneration in patients with massive rotator cuff tears are caused by SSN damage 34,35 . Rowshan et al 34 examined a rabbit subscapularis tenotomised model and concluded that fatty infiltration of the muscle occurs with chronic rotator cuff tears and may be explained by nerve injury.…”

Section: All Authors Contributed To the Conception Design And Prepamentioning

confidence: 99%

Suprascapular neuropathy related to rotator cuff tears: A short review

Yamaakdo¹

2013

OA Sports Medicine

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Introduction Suprascapular nerve neuropathy related to rotator cuff tears has become a topic of discussion. However, there are a few studies to support suprascapular nerve neuropathy in cases of (massive) rotator cuff tears. There are also a few studies showing the indication for concomitant suprascapular nerve release; however, several clinical and basic studies provide some evidence that suprascapular nerve injury may be a part of the disease spectrum of rotator cuff pathology. In this short review article, suprascapular neuropathy related to rotator cuff tears is discussed. Conclusion Till date, there are a few studies to support suprascapular nerve neuropathy in cases of (massive) rotator cuff tears. Future studies will hopefully serve to elucidate these issues.

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“…The purpose of this study was to examine the role of MMP-13 in rotator cuff muscle FI in following a massive rotator cuff tear. We employed MMP-13 null mice in a previously established rodent RC tears model 17,18 . We found that MMP-13 null mice have significantly worsen muscle FI compared to wildtype mice.…”

Section: Introductionmentioning

confidence: 99%

Knocking-out matrix metalloproteinase-13 exacerbates rotator cuff muscle fatty infiltration

Liu

Ravishankar

Ning

et al. 2017

MLTJ

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SummaryIntroduction: Rotator cuff (RC) tears are common tendon injuries. Clinically, both muscle atrophy and fatty infiltration have generally been attributed to poor functional outcomes. Matrix metalloproteinase-13 plays a crucial role in extracellular matrix remodeling in many physiological and pathological processes. Nevertheless, its role in rotator cuff muscle atrophy and fatty infiltration remains unknown. The purpose of this study is to define the functional role of MMP-13 in rotator cuff muscle atrophy and fatty infiltration using a mouse RC tears model. Materials and methods: Unilateral complete supraspinatus and infraspinatus tendon transection and suprascapular nerve transection was performed on nine of MMP-13 (-/-) knockout and nine of MMP-13 (+/+) wildtype mice at 3 months old. Mice were sacrificed 6 weeks after surgery. Supraspinatus (SS) and infraspinatus (IS) muscles were harvested for histology and gene expression analysis with RT-PCR. Results: Six weeks after RC surgery, no significant difference in muscle atrophy and fibrosis between MMP-13 knockout and wild type mice was observed. However, there was a significant increase in the amount of fatty infiltration in MMP-13 knockout mice compared to the wild types. Muscles from MMP-13 knockout mice have significantly higher expression of fatty infiltration related genes.

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A Mouse Model of Massive Rotator Cuff Tears

Cited by 97 publications

References 30 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

Suprascapular neuropathy related to rotator cuff tears: A short review

Knocking-out matrix metalloproteinase-13 exacerbates rotator cuff muscle fatty infiltration

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