Agustin Diaz, Luke Sang, Steven Garcia, Aboubacar Wague, Michael Davies, Alex Youn, Xuhui Liu, Brian T. Feeley
{"title":"在慢性肩袖修复的小鼠模型中,B3AR 激动剂介导的 FAP UCP-1 表达激活随年龄增长而下降。","authors":"Agustin Diaz, Luke Sang, Steven Garcia, Aboubacar Wague, Michael Davies, Alex Youn, Xuhui Liu, Brian T. Feeley","doi":"10.1002/jor.25905","DOIUrl":null,"url":null,"abstract":"<p>Amibegron, a β3-adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP-1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4-month-old) and aged (33-month-old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6-weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6-weeks post-DR. For in vitro histology and real-time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence-activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8-days after seeding (late exposure). In vitro results showed that amibegron-mediated FAP UCP-1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP-1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP-targeted therapeutics for chronic injuries.</p>","PeriodicalId":16650,"journal":{"name":"Journal of Orthopaedic Research®","volume":null,"pages":null},"PeriodicalIF":2.1000,"publicationDate":"2024-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jor.25905","citationCount":"0","resultStr":"{\"title\":\"Age-dependent decline of B3AR agonist-mediated activation of FAP UCP-1 expression in murine models of chronic rotator cuff repair\",\"authors\":\"Agustin Diaz, Luke Sang, Steven Garcia, Aboubacar Wague, Michael Davies, Alex Youn, Xuhui Liu, Brian T. Feeley\",\"doi\":\"10.1002/jor.25905\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Amibegron, a β3-adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP-1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4-month-old) and aged (33-month-old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6-weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6-weeks post-DR. For in vitro histology and real-time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence-activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8-days after seeding (late exposure). In vitro results showed that amibegron-mediated FAP UCP-1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP-1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP-targeted therapeutics for chronic injuries.</p>\",\"PeriodicalId\":16650,\"journal\":{\"name\":\"Journal of Orthopaedic Research®\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.1000,\"publicationDate\":\"2024-05-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jor.25905\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Orthopaedic Research®\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/jor.25905\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ORTHOPEDICS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Orthopaedic Research®","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jor.25905","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ORTHOPEDICS","Score":null,"Total":0}
Age-dependent decline of B3AR agonist-mediated activation of FAP UCP-1 expression in murine models of chronic rotator cuff repair
Amibegron, a β3-adrenergic receptor (B3AR) agonist, has recently been shown to provide therapeutic effects for chronic rotator cuff (RC) tears by inducing the expression of uncoupling protein 1 (UCP-1), a marker of brown fat, in fibroadipogenic progenitors (FAPs). However, it remains to be seen if these beneficial effects hold true with age and in older, more clinically relevant populations. This study seeks to understand the impacts of aging on the efficacy of amibegron to treat chronic RC tears. Young (4-month-old) and aged (33-month-old) C57BL/6 mice underwent a RC injury procedure with delayed repair (DR). Mice were equally randomized to receive amibegron or dimethyl sulfoxide (DMSO) treatments after repair. Functional ability was measured at baseline and 6-weeks after DR. Wet muscle weight and histology of injured and contralateral supraspinatus were also analyzed 6-weeks post-DR. For in vitro histology and real-time quantitative PCR experiments, FAPs were isolated from young and aged mice via fluorescence-activated cell sorting. Young and aged FAPs were treated with amibegron or DMSO either immediately after seeding (early exposure) or 8-days after seeding (late exposure). In vitro results showed that amibegron-mediated FAP UCP-1 expression decreases with age. In vivo data demonstrated that aged mice have a decreased responsiveness to amibegron and decreased propensity for intramuscular FAP UCP-1 expression. Further, delayed amibegron treatment with RC repair did not lead to improvements in muscle atrophy and functional outcomes. Our findings demonstrate that age and the timing of interventions play a critical role in FAP-targeted therapeutics for chronic injuries.
期刊介绍:
The Journal of Orthopaedic Research is the forum for the rapid publication of high quality reports of new information on the full spectrum of orthopaedic research, including life sciences, engineering, translational, and clinical studies.