Fatty acid-binding protein 4 regulates fatty infiltration after rotator cuff tear by hypoxia-inducible factor 1 in mice.
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TLDR
The role of FABP4, a carrier protein for fatty acids and is involved in fatty acid uptake, transport, and lipid metabolism, is examined in muscle fatty infiltration in an RCT mouse model.Abstract:
Background
Fatty 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.
Methods
In 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.
Results
FABP4 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.
Conclusions
This 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.read more
Citations
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FABP4 silencing ameliorates hypoxia reoxygenation injury through the attenuation of endoplasmic reticulum stress-mediated apoptosis by activating PI3K/Akt pathway.
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Is a Local Administration of Parathyroid Hormone Effective to Tendon-to-Bone Healing in a Rat Rotator Cuff Repair Model?
Jong Pil Yoon,Seok Won Chung,Jae Wook Jung,Yong-Soo Lee,Kwang-Il Kim,Ga Young Park,Hun-Min Kim,Jin-Hyun Choi +7 more
TL;DR: Local PTH administration using an absorbable scaffold improved the biomechanical and histological outcomes of rotator cuff tendon‐to‐bone healing comparable with systemic PTH injection at 8 weeks after repair in a rat model.
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Effect of hypercholesterolemia on fatty infiltration and the quality of tendon-to-bone healing in a rabbit model of a chronic rotator cuff tear: Electrophysiological, biomechanical, and histological analyses
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Evaluating the role of subacromial impingement in rotator cuff tendinopathy: Development and analysis of a novel murine model.
Guang-Ting Cong,Amir Lebaschi,Christopher L. Camp,Camila B. Carballo,Yusuke Nakagawa,Susumu Wada,Xiang-Hua Deng,Scott A. Rodeo +7 more
TL;DR: Overall, this novel murine subacromial impingement model creates changes consistent with acute tendonitis, which may mimic the early stages of rotator cuff tendinopathy.
References
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Fatty muscle degeneration in cuff ruptures. Pre- and postoperative evaluation by CT scan
TL;DR: A preoperative computed tomography scan grading muscular fatty degeneration in five stages was done in 63 patients scheduled for repair of a torn rotator cuff, finding that infraspinatus degeneration had a highly negative influence on the outcome of suprasp inatus repairs.
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Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle.
TL;DR: It is suggested that interaction between muscle cells and PDGFRα+ mesenchymal progenitors, not the fate decision of satellite cells, has a considerable impact on muscle homeostasis and is the major contributor to ectopic fat cell formation in skeletal muscle.
Journal ArticleDOI
Rotator-cuff changes in asymptomatic adults. The effect of age, hand dominance and gender
TL;DR: The results indicate that rotator-cuff lesions are a natural correlate of ageing, and are often present with no clinical symptoms, and should be treated based on clinical findings and not on the results of imaging.
Journal ArticleDOI
Fatty Infiltration and Atrophy of the Rotator Cuff Do Not Improve After Rotator Cuff Repair and Correlate With Poor Functional Outcome
TL;DR: It is suggested that repairs should be performed, if possible, before more significant deterioration in the cuff musculature in order to optimize outcomes, and that understanding the degree of muscle atrophy and fatty infiltration before surgery can help guide patient expectations.