Retinoic Acid Receptor Agonists Suppress Muscle Fatty Infiltration in Mice

Background: The infiltration of fat tissue into skeletal muscle, a condition referred to as muscle fatty infiltration or fatty degeneration, is regarded as an irreversible event that significantly compromises the motor function of skeletal muscle. Purpose: To investigate the effect of retinoic acid receptor (RAR) agonists in suppressing the adipogenic differentiation of fibroadipogenic progenitors (FAPs) in vitro and fatty infiltration after rotator cuff tear in mice. Study Design: Controlled laboratory study. Methods: FAPs isolated from mouse skeletal muscle were cultured in adipogenic differentiation medium in the presence or absence of an RAR agonist. At the end of cell culture, adipogenic differentiation was evaluated by gene expression analysis and oil red O staining. A mouse model of fatty infiltration—which includes the resection of the rotator cuff, removal of the humeral head, and denervation the supraspinatus muscle—was used to induce fatty infiltration in the supraspinatus muscle. The mice were orally or intramuscularly administered with an RAR agonist after the surgery. Muscle fatty infiltration was evaluated by histology and gene expression analysis. Results: RAR agonists effectively inhibited the adipogenic differentiation of FAPs in vitro. Oral and intramuscular administration of RAR agonists suppressed the development of muscle fatty infiltration in the mice after rotator cuff tear. In accordance, we found a significant decrease in the number of intramuscular fat cells and suppressed expression in adipogenic markers. RAR agonists also increased the expression of the transcripts for collagens; however, an accumulation of collagenous tissues was not histologically evident in the present model. Conclusion: Muscle fatty infiltration can be alleviated by RAR agonists through suppressing the adipogenic differentiation of FAPs. The results also suggest that RAR agonists are potential therapeutic agents for treating patients who are at risk of developing muscle fatty infiltration. The consequence of the increased expression of collagen transcripts by RAR agonists needs to be clarified. Clinical Relevance: RAR agonists can be used to prevent the development of muscle fatty infiltration after rotator cuff tear. Nevertheless, further studies are mandatory in a large animal model to examine the safety and efficacy of intramuscular injection of RAR agonists.

Download Full-text

Relationship between fatty infiltration and gene expression in patients with medium rotator cuff tear

Journal of Shoulder and Elbow Surgery ◽

10.1016/j.jse.2020.06.003 ◽

2020 ◽

Author(s):

Se-Young Ki ◽

Yong-Soo Lee ◽

Ja-Yeon Kim ◽

Taewoo Lho ◽

Seok Won Chung

Keyword(s):

Gene Expression ◽

Rotator Cuff ◽

Rotator Cuff Tear ◽

Fatty Infiltration ◽

Cuff Tear

Download Full-text

Gene Expression Patterns Analysis in the Supraspinatus Muscle after a Rotator Cuff Tear in a Mouse Model

BioMed Research International ◽

10.1155/2018/5859013 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 1

Author(s):

Yong-Soo Lee ◽

Ja-Yeon Kim ◽

Hyo-Nam Kim ◽

Dhong-Won Lee ◽

Seok Won Chung

Keyword(s):

Gene Expression ◽

Rotator Cuff ◽

Rotator Cuff Tear ◽

Expression Patterns ◽

Fatty Infiltration ◽

Rna Isolation ◽

Muscle Physiology ◽

Fatty Acid Transport ◽

Muscle Degeneration ◽

Cuff Tear

Rotator cuff tear is a muscle-tendinous injury representative of various musculoskeletal disorders. In general, rotator cuff tear occurs in the tendon, but it causes unloading of the muscle resulting in muscle degeneration including fatty infiltration. These muscle degenerations lead to muscle weakness, pain, and loss of shoulder function and are well known as important factors for poor functional outcome after rotator cuff repair. Given that rotator cuff tear in various animal species results in similar pathological changes seen in humans, the animal model can be considered a good approach to understand the many aspects of the molecular changes in injured muscle. To comprehensively analyze changes in gene expression with time following a rotator cuff tear, we established a rotator cuff tear in mouse supraspinatus tendon of shoulder. At weeks 1 and 4 after the tear, the injured muscles were harvested for RNA isolation, and microarray analysis was performed. Expression patterns of genes belonging to 10 muscle physiology-related categories, including aging, apoptosis, atrophy, and fatty acid transport, were analyzed and further validated using real-time PCR. A total of 39,429 genes were analyzed, and significant changes in expression were observed for 12,178 genes at 1 week and 2,370 genes at 4 weeks after the tear. From the list of top 10 significantly up- and downregulated genes at the 2 time periods and the network evaluation of relevant genes according to the 10 categories, several important genes in each category were observed. In this study, we found that various genes are significantly altered after rotator cuff tear, and these genes may play key roles in controlling muscle degeneration after a rotator cuff tear.

Download Full-text

Retinoic Acid Receptor Agonists Suppress Fatty Infiltration in a Mouse Model of Rotator Cuff Tear

Journal of Shoulder and Elbow Surgery ◽

10.1016/j.jse.2020.01.041 ◽

2020 ◽

Vol 29 (4) ◽

pp. e156-e158

Author(s):

Hideyuki Shirasawa ◽

Noboru Matsumura ◽

Satoshi Oki ◽

Morio Matsumoto ◽

Masaya Nakamura ◽

...

Keyword(s):

Retinoic Acid ◽

Rotator Cuff ◽

Mouse Model ◽

Rotator Cuff Tear ◽

Retinoic Acid Receptor ◽

Fatty Infiltration ◽

Acid Receptor ◽

Receptor Agonists ◽

Cuff Tear

Download Full-text

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

Journal of Cachexia Sarcopenia and Muscle ◽

10.1002/jcsm.12203 ◽

2017 ◽

Vol 8 (5) ◽

pp. 839-850 ◽

Cited By ~ 10

Author(s):

Yong-Soo Lee ◽

Ja-Yeon Kim ◽

Kyung-Soo Oh ◽

Seok Won Chung

Keyword(s):

Fatty Acid ◽

Rotator Cuff ◽

Rotator Cuff Tear ◽

Fatty Acid Binding Protein ◽

Fatty Infiltration ◽

Hypoxia Inducible Factor ◽

Fatty Acid Binding ◽

Hypoxia Inducible Factor 1 ◽

Acid Binding Protein ◽

Cuff Tear

Download Full-text

Rotator Cuff Tear Size Regulates Fibroadipogenic Progenitor Number and Gene Expression Profile in the Supraspinatus Independent of Patient Age

The American Journal of Sports Medicine ◽

10.1177/03635465211054512 ◽

2021 ◽

pp. 036354652110545

Author(s):

Michael R. Davies ◽

Hannah Chi ◽

Gurbani Kaur ◽

Mengyao Liu ◽

C. Benjamin Ma ◽

...

Keyword(s):

Gene Expression ◽

Rotator Cuff ◽

Rotator Cuff Tear ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Patient Age ◽

Cuff Tear ◽

Patient Âgé ◽

Beige Adipocytes ◽

Tear Size

Background: Fatty infiltration of rotator cuff muscle is a limiting factor in the success of repairs. Fibroadipogenic progenitors (FAPs) are a population of stem cells within the rotator cuff that can differentiate into white adipocytes, fibroblasts, and beige adipocytes. The effects of patient age and rotator cuff tendon tear size on the number, differentiation patterns, and gene expression profiles of FAPs have not yet been analyzed. Purpose: To determine if patient age and rotator cuff tear size independently regulate FAP number, differentiation patterns, and gene expression profiles. Study Design: Controlled laboratory study. Methods: Supraspinatus muscle samples were collected from 26 patients between the ages of 42 and 76 years with partial- or full-thickness rotator cuff tears. FAPs were quantified using fluorescence-activated cell sorting. Gene expression analysis was performed across a custom 96-gene panel using NanoString. In vitro differentiation assays of FAPs were conducted using adipogenic, fibrogenic, and beige-inducing (amibegron-treated) media, and quantitative polymerase chain reaction was used to assess gene expression differences between adipogenic and amibegron media conditions. Multivariable linear regressions were performed using Stata to independently analyze the effects of age and rotator cuff tear size on FAP number, differentiation, and gene expression. Results: Increasing age and tear size were independently correlated with increased FAP number (βage = 0.21, P = .03; βtear size = 3.86, P = .05). There was no clear association between age and gene expression of freshly sorted FAPs. Under adipogenic and fibrogenic media conditions, increasing age and tear size were independently associated with increased adipogenic and fibrogenic differentiation of FAPs. Under amibegron treatment conditions, age positively correlated with increased beige differentiation (β = 1.03; P < .0001), while increasing tear size showed a trend toward decreased beige differentiation (β = −4.87; P = .1). When gene expression patterns between adipogenic and amibegron media conditions were compared, larger tear size strongly inhibited beige gene expression, while advanced age did not. Conclusion: Patient age and rotator cuff tear size independently regulated FAP number, differentiation, and gene expression. Age and tear size were positively correlated with increased FAP number and fibrogenic/adipogenic differentiation. Advancing patient age did not limit FAP beige differentiation and gene expression, while increasing rotator cuff tear size strongly inhibited these processes.

Download Full-text

MicroRNA-29a Mitigates Subacromial Bursa Fibrosis in Rotator Cuff Lesion with Shoulder Stiffness

International Journal of Molecular Sciences ◽

10.3390/ijms20225742 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5742 ◽

Cited By ~ 1

Author(s):

Jih-Yang Ko ◽

Wei-Shiung Lian ◽

Tsai-Chen Tsai ◽

Yu-Shan Chen ◽

Chin-Kuei Hsieh ◽

...

Keyword(s):

Rotator Cuff ◽

Rotator Cuff Tear ◽

Shoulder Function ◽

Pathological Feature ◽

Subacromial Bursa ◽

Shoulder Disorder ◽

Shoulder Stiffness ◽

Cuff Tear ◽

Rotator Cuff Lesion

Rotator cuff lesion with shoulder stiffness is a major cause of shoulder pain and motionlessness. Subacromial bursa fibrosis is a prominent pathological feature of the shoulder disorder. MicroRNA-29a (miR-29a) regulates fibrosis in various tissues; however, the miR-29a action to subacromial bursa fibrosis remains elusive. Here, we reveal that subacromial synovium in patients with rotator cuff tear with shoulder stiffness showed severe fibrosis, hypertrophy, and hyperangiogenesis histopathology along with significant increases in fibrotic matrices collagen (COL) 1A1, 3A1, and 4A1 and inflammatory cytokines, whereas miR-29a expression was downregulated. Supraspinatus and infraspinatus tenotomy-injured shoulders in transgenic mice overexpressing miR-29a showed mild swelling, vascularization, fibrosis, and regular gait profiles as compared to severe rotator cuff damage in wild-type mice. Treatment with miR-29a precursor compromised COL3A1 production and hypervascularization in injured shoulders. In vitro, gain of miR-29a function attenuated COL3A1 expression through binding to the 3’-untranslated region (3′-UTR) of COL3A1 in inflamed tenocytes, whereas silencing miR-29a increased the matrix expression. Taken together, miR-29a loss is correlated with subacromial bursa inflammation and fibrosis in rotator cuff tear with shoulder stiffness. miR-29a repressed subacromial bursa fibrosis through directly targeting COL3A1 mRNA, improving rotator cuff integrity and shoulder function. Collective analysis offers a new insight into the molecular mechanism underlying rotator cuff tear with shoulder stiffness. This study also highlights the remedial potential of miR-29a precursor for alleviating the shoulder disorder.

Download Full-text