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Journal of Cachexia Sarcopenia and Muscle最新文献

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The Prognostic Value of Sarcopenia in Clinical Outcomes in Cervical Cancer: A Systematic Review and Meta-Analysis 骨骼肌减少症对宫颈癌临床预后的预测价值:一项系统综述和荟萃分析
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-11 DOI: 10.1002/jcsm.13674
Fang Wang, Hongnan Zhen, Kang Yu, Pengju Liu
<div> <section> <h3> Background</h3> <p>Sarcopenia is a condition characterized by inadequate muscle and function decline and is often associated with ageing and cancer. It is established that sarcopenia and muscle loss occurred during treatment are associated with the clinical outcomes of patients with cancer. This systematic review and meta-analysis aims to evaluate the association between sarcopenia at pretreatment and during treatment and overall survival or disease progression in patients with cervical cancer.</p> </section> <section> <h3> Methods</h3> <p>The Web of Science, Embase, Medline and Cochrane Library databases were searched until 4 July 2024. Studies evaluating the prognostic effect of muscle mass at pretreatment or muscle change during treatment on survival or disease progression for patients with cervical cancer were included. Study quality was evaluated with the Newcastle–Ottawa Scale (NOS). Forest plots and summary effect models were used to show the effect size of sarcopenia on clinical outcomes.</p> </section> <section> <h3> Results</h3> <p>The search strategy yielded 1721 studies in four databases. Eleven and seven studies were included in the quantitative analysis of pretreatment sarcopenia and muscle change on clinical outcomes, respectively. A total of 1907 patients underwent pretreatment muscle assessment, but 1016 were monitored for muscle changes; however, none of the studies involved measures of muscle strength or function. Meta-analysis showed a significant association between pretreatment sarcopenia and OS [hazard ratio (HR) 1.58, 95% confidence interval (CI): 1.16–2.14, <i>p</i> = 0.003] and PFS (HR 1.63, 95%CI 1.16–2.29, <i>p</i> = 0.005) according to data of univariate analysis. In the meta-analysis of the multivariate data, pretreatment sarcopenia remained associated with poor OS (HR 3.09, 95% CI: 2.07–4.61, <i>p</i> < 0.00001) and PFS (HR: 1.55, 95%CI 1.06–2.28, <i>p</i> = 0.03). Additionally, muscle loss was significantly associated with OS (HR 5.18, 95%CI 3.54–7.56, <i>p</i> < 0.00001) and PFS (HR 2.62, 95%CI 1.63–4.22, <i>p</i> < 0.00001). Subgroup analysis showed that the association between pretreatment sarcopenia and OS, as well as PFS, was influenced by muscle mass measurements and cut-off values, whereas muscle loss consistently predicted worse OS and PFS when stratified by varying degrees of reduction. The NOS scores of all included studies were ≥ 6.</p> </section> <section> <h3> Conclusions</h3> <p>Pretreatment sarcopenia and muscle change during treatment are significantly associated with bot
肌肉减少症是一种以肌肉不足和功能下降为特征的疾病,通常与衰老和癌症有关。研究证实,治疗期间发生的肌肉减少和肌肉损失与癌症患者的临床预后有关。本系统综述和荟萃分析旨在评估宫颈癌患者治疗前和治疗期间肌肉减少症与总生存期或疾病进展之间的关系。
{"title":"The Prognostic Value of Sarcopenia in Clinical Outcomes in Cervical Cancer: A Systematic Review and Meta-Analysis","authors":"Fang Wang,&nbsp;Hongnan Zhen,&nbsp;Kang Yu,&nbsp;Pengju Liu","doi":"10.1002/jcsm.13674","DOIUrl":"10.1002/jcsm.13674","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Sarcopenia is a condition characterized by inadequate muscle and function decline and is often associated with ageing and cancer. It is established that sarcopenia and muscle loss occurred during treatment are associated with the clinical outcomes of patients with cancer. This systematic review and meta-analysis aims to evaluate the association between sarcopenia at pretreatment and during treatment and overall survival or disease progression in patients with cervical cancer.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The Web of Science, Embase, Medline and Cochrane Library databases were searched until 4 July 2024. Studies evaluating the prognostic effect of muscle mass at pretreatment or muscle change during treatment on survival or disease progression for patients with cervical cancer were included. Study quality was evaluated with the Newcastle–Ottawa Scale (NOS). Forest plots and summary effect models were used to show the effect size of sarcopenia on clinical outcomes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The search strategy yielded 1721 studies in four databases. Eleven and seven studies were included in the quantitative analysis of pretreatment sarcopenia and muscle change on clinical outcomes, respectively. A total of 1907 patients underwent pretreatment muscle assessment, but 1016 were monitored for muscle changes; however, none of the studies involved measures of muscle strength or function. Meta-analysis showed a significant association between pretreatment sarcopenia and OS [hazard ratio (HR) 1.58, 95% confidence interval (CI): 1.16–2.14, &lt;i&gt;p&lt;/i&gt; = 0.003] and PFS (HR 1.63, 95%CI 1.16–2.29, &lt;i&gt;p&lt;/i&gt; = 0.005) according to data of univariate analysis. In the meta-analysis of the multivariate data, pretreatment sarcopenia remained associated with poor OS (HR 3.09, 95% CI: 2.07–4.61, &lt;i&gt;p&lt;/i&gt; &lt; 0.00001) and PFS (HR: 1.55, 95%CI 1.06–2.28, &lt;i&gt;p&lt;/i&gt; = 0.03). Additionally, muscle loss was significantly associated with OS (HR 5.18, 95%CI 3.54–7.56, &lt;i&gt;p&lt;/i&gt; &lt; 0.00001) and PFS (HR 2.62, 95%CI 1.63–4.22, &lt;i&gt;p&lt;/i&gt; &lt; 0.00001). Subgroup analysis showed that the association between pretreatment sarcopenia and OS, as well as PFS, was influenced by muscle mass measurements and cut-off values, whereas muscle loss consistently predicted worse OS and PFS when stratified by varying degrees of reduction. The NOS scores of all included studies were ≥ 6.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Pretreatment sarcopenia and muscle change during treatment are significantly associated with bot","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13674","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ergogenic Benefits of β-Hydroxy-β-Methyl Butyrate (HMB) Supplementation on Body Composition and Muscle Strength: An Umbrella Review of Meta-Analyses 补充β -羟基- β -丁酸甲酯(HMB)对身体成分和肌肉力量的有益作用:荟萃分析综述
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-10 DOI: 10.1002/jcsm.13671
Mohammad Vesal Bideshki, Mehrdad Behzadi, Mehrdad Jamali, Parsa Jamilian, Meysam Zarezadeh, Bahram Pourghassem Gargari

Background

β-Hydroxy-β-methyl butyrate (HMB) is a metabolite of the amino acid leucine, known for its ergogenic effects on body composition and strength. Despite these benefits, the magnitude of these effects remains unclear due to variability among studies. This umbrella review aims to synthesize meta-analyses investigating the effects of HMB on body composition and muscle strength in adults.

Methods

A comprehensive literature search was conducted in Scopus, PubMed and Web of Science without date or language restrictions until August 2024. The study protocol was registered at Prospero (No. CRD42023402740). Included studies evaluated the effects of HMB supplementation on body mass, fat mass (FM), fat-free mass (FFM), muscle mass and performance outcomes. Effect sizes (ESs) and 95% confidence intervals (CIs) were calculated, and a random-effects model was used for meta-analysis. Standard methods assessed heterogeneity, sensitivity and publication bias. The methodological quality of included studies was assessed using the AMSTAR2 tool.

Results

Eleven studies comprising 41 data sets were included, with participants aged 23–79 years. HMB supplementation significantly increased muscle mass (ES: 0.21; 95% CI: 0.06–0.35; p = 0.004), muscle strength index (ES: 0.27; 95% CI: 0.19–0.35; p < 0.001) and FFM (ES: 0.22; 95% CI: 0.11–0.34; p < 0.001). No significant changes were observed in FM (ES: 0.03; 95% CI: −0.04 to 0.35; p = 0.09) or body mass (ES: 0.09; 95% CI: −0.06 to 0.24; p = 0.22). The quality assessment revealed that five studies were of high quality, three were of low quality and three were of critically low quality.

Conclusions

HMB supplementation may benefit individuals experiencing muscular atrophy due to physiological conditions, particularly enhancing muscle mass and strength without significant changes in fat mass or body weight.

β -羟基- β -丁酸甲酯(HMB)是氨基酸亮氨酸的代谢物,以其对身体成分和力量的促氧作用而闻名。尽管有这些好处,但由于研究之间的差异,这些影响的程度仍不清楚。本综述旨在综合meta分析,研究HMB对成人身体成分和肌肉力量的影响。方法于2024年8月前在Scopus、PubMed和Web of Science中进行无日期和语言限制的综合文献检索。研究方案已在普洛斯彼罗(普洛斯彼罗)登记。CRD42023402740)。纳入的研究评估了补充HMB对体重、脂肪质量(FM)、无脂肪质量(FFM)、肌肉质量和表现结果的影响。计算效应量(ESs)和95%置信区间(ci),并采用随机效应模型进行meta分析。标准方法评估异质性、敏感性和发表偏倚。使用AMSTAR2工具评估纳入研究的方法学质量。结果纳入41个数据集的11项研究,参与者年龄在23-79岁之间。添加HMB显著增加肌肉质量(ES: 0.21;95% ci: 0.06-0.35;p = 0.004),肌力指数(ES: 0.27;95% ci: 0.19-0.35;p & lt;0.001)和FFM (ES: 0.22;95% ci: 0.11-0.34;p & lt;0.001)。FM无显著变化(ES: 0.03;95% CI:−0.04 ~ 0.35;p = 0.09)或体重(ES: 0.09;95% CI:−0.06 ~ 0.24;P = 0.22)。质量评估显示,5项研究为高质量,3项为低质量,3项为极低质量。结论补充shmb可能对因生理条件而出现肌肉萎缩的个体有益,特别是在不显著改变脂肪量或体重的情况下增加肌肉质量和力量。
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引用次数: 0
Cut-Off Points for Low Relative 30-s Sit-to-Stand Power and Their Associations With Adverse Health Conditions 相对30岁坐立比低的分界点及其与不良健康状况的关系
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-10 DOI: 10.1002/jcsm.13676
Mikel Garcia-Aguirre, Ivan Baltasar-Fernandez, Julian Alcazar, Jose Losa-Reyna, Ana Alfaro-Acha, Ignacio Ara, Leocadio Rodriguez-Mañas, Luis M. Alegre, Francisco J. Garcia-Garcia

Background

Despite muscle power derived from the 5-rep sit-to-stand (STS) test having been demonstrated to be a valuable biomarker in older individuals, there is limited information regarding muscle power derived from the 30-s STS test, a widely used test in the clinical setting. This study aimed (i) to compare relative 30-s STS power values between older men and women, (ii) to identify cut-off points for low relative 30-s STS power, (iii) to compare the prevalence of low relative STS power between sexes and (iv) to evaluate the association of low relative 30-s STS power with adverse conditions in older people.

Methods

A total of 1475 community-dwelling older adults (65–98 years; 45% men) from the Toledo Study for Healthy Aging were included. Relative STS power was assessed using the 30-s STS test and the Alcazar's equation. Adverse health conditions considered encompassed frailty, depression, disability in basic (BADL) and instrumental activities of daily living (IADL), cognitive impairment and low habitual gait speed (HGS).

Results

Relative STS power decreased linearly at an average rate of 1.0% year−1 in men and 1.5% year−1 in women. The cut-off points for low relative STS power were 2.53 and 2.01 W·kg−1 for men and women, respectively. The prevalence of low relative STS power was significantly lower in older men compared with older women (43.5% vs. 50.0%, respectively; p = 0.005). In men, low relative STS power was associated with frailty (OR [95% CI] = 4.4 [2.4–8.0]), cognitive impairment (OR [95% CI] = 1.7 [1.0–2.7]), disability in BADL (OR [95% CI] = 4.5 [1.5–13.8]) and low HGS (OR [95% CI] = 3.4 [1.9–5.9]). In women, low relative STS power was associated with frailty (OR [95% CI] = 5.2 [3.5–7.7]), disability in BADL (OR [95% CI] = 4.3 [1.8–9.9]) and IADL (OR [95% CI] = 3.1 [2.2–4.3]) and low HGS (OR [95% CI] = 6.1 [2.8–13.1]). No associations were found between low relative STS power and disability in IADL or depression in men, nor between low relative STS power and cognitive impairment or depression in women.

Conclusion

Relative STS power decreased with increasing age in both men and women. The provided sex-specific cut-off points for low relative STS power using the 30-s STS test adequately identified older people with frailty and were associated with an increased risk of experiencing adverse conditions.

尽管从5次坐立(STS)测试中获得的肌肉力量已被证明是老年人中有价值的生物标志物,但关于从30秒STS测试中获得的肌肉力量的信息有限,这是一项在临床环境中广泛使用的测试。本研究旨在(i)比较老年男性和女性的相对30-s STS功率值,(ii)确定低相对30-s STS功率的分界点,(iii)比较低相对STS功率在性别之间的患病率,以及(iv)评估低相对30-s STS功率与老年人不利条件的关系。
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引用次数: 0
Reference Values of Handgrip and Lower Extremity Strength for Vietnamese Men and Women: The Vietnam Osteoporosis Study 越南男性和女性握力和下肢力量的参考值:越南骨质疏松症研究
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-10 DOI: 10.1002/jcsm.13689
Kiet T. Do, Duy K. Hoang, Quan N. Luong, Huy G. Nguyen, An T. Do, Lan T. Ho-Pham, Tuan V. Nguyen

Background

Falls and sarcopenia are significant public health issues in Vietnam. Despite muscle strength being a critical predictor for these conditions, reference data on muscle strength within the Vietnamese population are lacking.

Purpose

To establish the reference ranges for muscle strength among Vietnamese individuals.

Methods

The study involved 4096 individuals, including 1419 men and 2677 women aged 18 years and above, from the Vietnam Osteoporosis Study. Muscle strength was assessed using a Baseline hand dynamometer for handgrip strength and a Back-Leg-Chest dynamometer for leg strength. We calculated mean values, standard deviations, interquartile ranges, and peak muscle strength (pMS) for both handgrip and leg strength across various ages. Reference curves were created with the Generalised Additive Model for Location Scale and Shape, and polynomial regression models were employed to analyse the relationship between muscle strength and age.

Results

Advancing age was significantly associated with lower muscle strength. Peak muscle strength typically occurred between ages 30 and 40, with earlier peaks in women, especially in leg strength. Men consistently showed higher muscle strength than women, with variations depending on the measurement site. Specifically, average handgrip strength was 36.4 kg ± 8.4 (mean ± SD) for men and 23.2 kg ± 6.0 for women (p < 0.001). Leg strength averaged 63.9 kg ± 27.2 for men and 29.5 kg ± 13.9 for women (p < 0.001). Additionally, we produced a percentile chart illustrating muscle weakness ranges based on the 25th percentile of muscle strength and the appendicular skeletal muscle mass index (ASMI) for the Vietnamese population.

Conclusion

These data provide reference ranges for evaluating muscle strength in the Vietnamese population, offering crucial insights for identifying individuals at risk of falls or sarcopenia in clinical settings.

跌倒和肌肉减少症是越南重大的公共卫生问题。尽管肌肉力量是这些疾病的关键预测指标,但越南人口中肌肉力量的参考数据缺乏。
{"title":"Reference Values of Handgrip and Lower Extremity Strength for Vietnamese Men and Women: The Vietnam Osteoporosis Study","authors":"Kiet T. Do,&nbsp;Duy K. Hoang,&nbsp;Quan N. Luong,&nbsp;Huy G. Nguyen,&nbsp;An T. Do,&nbsp;Lan T. Ho-Pham,&nbsp;Tuan V. Nguyen","doi":"10.1002/jcsm.13689","DOIUrl":"10.1002/jcsm.13689","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Falls and sarcopenia are significant public health issues in Vietnam. Despite muscle strength being a critical predictor for these conditions, reference data on muscle strength within the Vietnamese population are lacking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>To establish the reference ranges for muscle strength among Vietnamese individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The study involved 4096 individuals, including 1419 men and 2677 women aged 18 years and above, from the Vietnam Osteoporosis Study. Muscle strength was assessed using a Baseline hand dynamometer for handgrip strength and a Back-Leg-Chest dynamometer for leg strength. We calculated mean values, standard deviations, interquartile ranges, and peak muscle strength (<i>p</i>MS) for both handgrip and leg strength across various ages. Reference curves were created with the Generalised Additive Model for Location Scale and Shape, and polynomial regression models were employed to analyse the relationship between muscle strength and age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Advancing age was significantly associated with lower muscle strength. Peak muscle strength typically occurred between ages 30 and 40, with earlier peaks in women, especially in leg strength. Men consistently showed higher muscle strength than women, with variations depending on the measurement site. Specifically, average handgrip strength was 36.4 kg ± 8.4 (mean ± SD) for men and 23.2 kg ± 6.0 for women (<i>p</i> &lt; 0.001). Leg strength averaged 63.9 kg ± 27.2 for men and 29.5 kg ± 13.9 for women (<i>p</i> &lt; 0.001). Additionally, we produced a percentile chart illustrating muscle weakness ranges based on the 25th percentile of muscle strength and the appendicular skeletal muscle mass index (ASMI) for the Vietnamese population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These data provide reference ranges for evaluating muscle strength in the Vietnamese population, offering crucial insights for identifying individuals at risk of falls or sarcopenia in clinical settings.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13689","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging 铁螯合可预防Klotho基因突变小鼠(衰老遗传模型)中与年龄相关的骨骼肌肌肉减少症
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-10 DOI: 10.1002/jcsm.13678
Chhanda Bose, Judit Megyesi, Oleg Karaduta, Sharda P. Singh, Sundararaman Swaminathan, Sudhir V. Shah
<div> <section> <h3> Background</h3> <p>A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice.</p> </section> <section> <h3> Methods</h3> <p>We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (<i>kl/kl</i>), an established mouse model for aging. Four weeks old Klotho <sup>−/−</sup> male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8–14 weeks (<i>n</i> = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods.</p> </section> <section> <h3> Results</h3> <p>Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (<i>p</i> < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both <i>p</i> < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (<i>p</i> = 0.019) and serum (<i>p</i> = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, <i>p</i> = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (<i>p</i> < 0.0001, <i>p</i> = 0.005), respectively, and elevated insulin-like growth factor levels (<i>p</i> = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (<i>p</i> < 0.001, <i>p</i> = 079), respectively. Significant weight loss (<i>p</i> < 0.001) and decreased water intake (<i>p</i> = 0.012) were observed in untreated mice compared to treatment group. Kaplan–Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (<i>p</i> = 0.0002).</p> </section>
骨骼肌质量和功能的下降被称为骨骼肌肌肉减少症,是衰老的必然结果。肌肉减少症是肌肉力量下降、身体虚弱和肌肉疲劳增加的主要原因,大大增加了老年人身体残疾和功能依赖的风险。仍然需要一种新的治疗方法来改善肌肉减少症和与衰老相关的问题。铁的积累,特别是通过氧化应激增加的催化铁(不稳定铁),可能是导致肌肉减少症的因素之一。我们的研究旨在研究铁螯合剂对小鼠年龄相关性肌肉减少症的影响。方法以衰老小鼠模型klotho缺乏症(kl/kl)为实验对象,研究铁螯合剂(DFP)对肌肉减少症的治疗作用。4周龄Klotho - / -雄性小鼠饮水中加入25 mg/kg体重的铁螯合剂去铁嘧啶,连续8-14周(每组12只,治疗组和未治疗组)。研究结束时,解剖腓肠肌、股四头肌和肱二头肌,进行western blot和免疫组化分析、组织病理学和铁染色。血清总铁、催化铁和细胞因子elisa采用既定方法。结果DFP治疗可显著减少腓肠肌和股四头肌肌肉质量损失(p <;0.0001)。血清总铁含量、催化铁含量和肌肉铁含量均显著高于对照组(p <;0.0001)更低。治疗8周后,肌生成抑制因子、腓肠肌肌生长抑制素蛋白(p = 0.019)和血清(p = 0.003)下调,肌肉收缩蛋白肌球蛋白重链增加(约2.9倍,p = 0.0004)。治疗降低炎症(血清il - 6和tnf - α) (p <;0.0001, p = 0.005),胰岛素样生长因子水平升高(p = 0.472)。这与减少DNA损伤和减少肌肉和HO - 1蛋白中的8 -羟基2脱氧鸟苷有关(p <;0.001, p = 079)。显著减肥(p <;与治疗组相比,未治疗组小鼠的饮水量减少(p = 0.012)。Kaplan-Meier生存曲线显示,治疗小鼠的中位寿命为108天,而未治疗小鼠的中位寿命为63天(p = 0.0002)。综上所述,我们的研究结果表明,去铁素可减少Klotho - / -小鼠肌肉中与年龄相关的肌肉减少症。我们的发现表明螯合过量的铁可能是对抗肌肉减少症的有效疗法。然而,需要进一步的研究来评估和确定其对人类的功效。
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引用次数: 0
Adeno-Associated Virus 8 and 9 Myofibre Type/Size Tropism Profiling Reveals Therapeutic Effect of Microdystrophin in Canines 腺相关病毒8和9肌纤维类型/大小嗜性分析揭示微肌营养不良蛋白对犬的治疗作用
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-10 DOI: 10.1002/jcsm.13681
Matthew J. Burke, Braiden M. Blatt, James A. Teixeira, Dennis O. Pérez-López, Yongping Yue, Xiufang Pan, Chady H. Hakim, Gang Yao, Roland W. Herzog, Dongsheng Duan

Background

Adeno-associated virus (AAV) 8 and 9 are in clinical trials for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). Muscle consists of myofibres of different types and sizes. However, little is known about the fibre type and fibre size tropism of AAV in large mammals.

Methods

We evaluated fibre type- and size-specific transduction properties of AAV8 and AAV9 in 17 dogs that received systemic gene transfer (dose 1.94 ± 0.52 × 1014 vg/kg; injected at 2.86 ± 0.30 months; harvested at 20.79 ± 3.30 months). For AAV8, two DMD dogs and three carrier dogs received an alkaline phosphatase (AP) reporter vector, and five DMD dogs received a four-repeat microdystrophin (uDys) vector. For AAV9, one normal and one DMD dog received the AP vector, and five DMD dogs received a five-repeat uDys vector. Association between AAV transduction and the fibre type/size was studied in three muscles that showed mosaic transgene expression, including the biceps femoris, teres major and latissimus dorsi.

Results

Transgene expression was detected in 30%–45% of myofibres. In the AP reporter vector–injected dogs, neither AAV8 nor AAV9 showed a statistically significant fibre type preference. Interestingly, AP expression was enriched in smaller fibres. In uDys-treated DMD dogs, slow and fast myofibres were equally transduced. Notably, uDys-expressing myofibres were significantly larger than uDys-negative myofibres irrespective of the AAV serotype (p < 0.0001). In AAV8 uDys vector–injected dogs, the mini-Feret diameter was 15%, 16% and 23% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 30%, 34% and 46% larger in uDys-positive slow, fast and hybrid fibres, respectively. In AAV9 uDys vector–injected dogs, the mini-Feret diameter was 12%, 13% and 25% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 25%, 28% and 59% larger in uDys-positive slow, fast and hybrid fibres, respectively.

Conclusions

Our studies suggest that AAV8 and AAV9 transduce fast and slow myofibres at equivalent efficiency. Importantly, uDys therapy effectively prevented dystrophic myofibre atrophy. Our study provides important insight into systemic muscle AAV delivery in large mammals and supports further development of uDys gene therapy for DMD.

腺相关病毒(AAV) 8和9正在临床试验中,用于治疗神经肌肉疾病,如杜氏肌营养不良(DMD)。肌肉由不同类型和大小的肌纤维组成。然而,对大型哺乳动物AAV的纤维类型和纤维大小倾向性知之甚少。
{"title":"Adeno-Associated Virus 8 and 9 Myofibre Type/Size Tropism Profiling Reveals Therapeutic Effect of Microdystrophin in Canines","authors":"Matthew J. Burke,&nbsp;Braiden M. Blatt,&nbsp;James A. Teixeira,&nbsp;Dennis O. Pérez-López,&nbsp;Yongping Yue,&nbsp;Xiufang Pan,&nbsp;Chady H. Hakim,&nbsp;Gang Yao,&nbsp;Roland W. Herzog,&nbsp;Dongsheng Duan","doi":"10.1002/jcsm.13681","DOIUrl":"10.1002/jcsm.13681","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Adeno-associated virus (AAV) 8 and 9 are in clinical trials for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). Muscle consists of myofibres of different types and sizes. However, little is known about the fibre type and fibre size tropism of AAV in large mammals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We evaluated fibre type- and size-specific transduction properties of AAV8 and AAV9 in 17 dogs that received systemic gene transfer (dose 1.94 ± 0.52 × 10<sup>14</sup> vg/kg; injected at 2.86 ± 0.30 months; harvested at 20.79 ± 3.30 months). For AAV8, two DMD dogs and three carrier dogs received an alkaline phosphatase (AP) reporter vector, and five DMD dogs received a four-repeat microdystrophin (uDys) vector. For AAV9, one normal and one DMD dog received the AP vector, and five DMD dogs received a five-repeat uDys vector. Association between AAV transduction and the fibre type/size was studied in three muscles that showed mosaic transgene expression, including the biceps femoris, teres major and latissimus dorsi.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Transgene expression was detected in 30%–45% of myofibres. In the AP reporter vector–injected dogs, neither AAV8 nor AAV9 showed a statistically significant fibre type preference. Interestingly, AP expression was enriched in smaller fibres. In uDys-treated DMD dogs, slow and fast myofibres were equally transduced. Notably, uDys-expressing myofibres were significantly larger than uDys-negative myofibres irrespective of the AAV serotype (<i>p</i> &lt; 0.0001). In AAV8 uDys vector–injected dogs, the mini-Feret diameter was 15%, 16% and 23% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 30%, 34% and 46% larger in uDys-positive slow, fast and hybrid fibres, respectively. In AAV9 uDys vector–injected dogs, the mini-Feret diameter was 12%, 13% and 25% larger in uDys-positive slow, fast and hybrid fibres, respectively; the cross-sectional area was 25%, 28% and 59% larger in uDys-positive slow, fast and hybrid fibres, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our studies suggest that AAV8 and AAV9 transduce fast and slow myofibres at equivalent efficiency. Importantly, uDys therapy effectively prevented dystrophic myofibre atrophy. Our study provides important insight into systemic muscle AAV delivery in large mammals and supports further development of uDys gene therapy for DMD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13681","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Large Variations in Phenylalanine Concentrations Associate Adverse Cardiac Remodelling in Adult Patients With Phenylketonuria—A Long-Term CMR Study 苯丙氨酸浓度的巨大变化与苯丙酮尿成年患者不良心脏重构相关——一项长期CMR研究
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2025-01-10 DOI: 10.1002/jcsm.13667
Radu Tanacli, Patrick Doeblin, Alessandro Faragli, Jan-Hendrik Hassel, Christian Stehning, Ursula Plöckinger, Athanasia Ziagaki, Sebastian Kelle
<div> <section> <h3> Background</h3> <p>Despite a phenylalanine (Phe) restrictive diet, most adult patients with ‘classical’ phenylketonuria (PKU) maintain life-long Phe concentrations above the normal range and receive tyrosine (Tyr) and protein-enriched diets to maintain acceptable concentrations and ensure normal development. While these interventions are highly successful in preventing adverse neuropsychiatric complications, their long- term consequences are incompletely explored. We observed early cardiomyopathic characteristics and associated hemodynamic changes in adult PKU patients and present here the results of a longitudinal evaluation of cardiac phenotype.</p> </section> <section> <h3> Methods</h3> <p>Fifteen adult patients with PKU (age: 39.8 ± 8.1 years, 9 males and 6 females) underwent a comprehensive follow-up cardiac magnetic resonance (CMR) imaging assessment after a mean follow-up interval of 8.3 ± 0.3 years from the initial baseline visit. The CMR protocol included left (LV) and right (RV) ventricular and left atrial (LA) volumetric assessment, LV parametric mapping (precontrast and postcontrast T1 and T2 maps, extracellular volume [ECV]), multilayer LV myocardial strain, systolic and diastolic hemodynamic forces and RV and LA strain and aortic distensibility evaluation. Plasma concentrations of Phe, tyrosine (Tyr) and other biochemical markers of disease were retrospectively collected. For comparison, a group of 20 matched control subjects undergoing an identical CMR protocol was included.</p> </section> <section> <h3> Results</h3> <p>On average, the LV end-diastolic volume (EDV) (158 ± 29 vs. 143 ± 29 mL, <i>p</i> = 0.013) and end-systolic volume (ESV) (68 ± 18 vs. 62 ± 18 mL, <i>p</i> = 0.011) were lower at follow-up. In contrast, LV mass (LVM) (72 ± 25 vs. 82 ± 29 g, <i>p</i> < 0.001) and the ratio LVM/EDV (0.46 ± 0.12 vs. 0.58 ± 0.23 g/mL, <i>p</i> = 0.005) were increased, and T1 times were longer (940 ± 42 vs. 1010 ± 35 ms, <i>p</i> < 0.001). LV EF (57 ± 6 vs. 57 ± 7%, <i>p</i> = 0.90), longitudinal (GLS) and circumferential (GCS) systolic strain remained unchanged, but early diastolic hemodynamic (HD) forces were more markedly negative (−19.4 ± 7.0 vs. −26.5 ± 12.2%, <i>p</i> = 0.012), while LA strain 43.8 ± 11.3 vs. 37.3 ± 9.6%, <i>p</i> = 0.031) and aortic distensibility (6.38 ± 1.75 vs. 5.21 ± 1.17 10<sup>−3</sup> mmHg<sup>−1</sup>, <i>p</i> = 0.008) decreased at follow-up. Compared with controls, PKU patients maintain reduced systolic function with lower LV EF and impaired GCS and have more markedly negative early diastolic HD pressures. A higher decrease in Phe concentration (ΔPhe) was associated with longer T1
背景:尽管采用苯丙氨酸(Phe)限制性饮食,大多数“经典”苯丙酮尿症(PKU)的成年患者终生将苯丙氨酸(Phe)浓度维持在正常范围以上,并接受酪氨酸(Tyr)和富含蛋白质的饮食以维持可接受的浓度并确保正常发育。虽然这些干预措施在预防不良的神经精神并发症方面非常成功,但其长期后果尚未完全探索。我们观察了成年PKU患者的早期心肌病特征和相关的血流动力学变化,并在此提出了心脏表型的纵向评估结果。方法对15例成年PKU患者(年龄:39.8±8.1岁,男9例,女6例)进行了全面的心脏磁共振(CMR)成像随访,平均随访时间为8.3±0.3年。CMR方案包括左(LV)和右(RV)心室和左心房(LA)容量评估,左室参数制图(对比前和对比后T1和T2图,细胞外体积[ECV]),多层左室心肌应变,收缩和舒张血流动力学力以及左室和左室应变和主动脉扩张性评估。回顾性收集Phe、酪氨酸(Tyr)及其他疾病生化指标的血浆浓度。为了进行比较,包括一组20名匹配的对照组,接受相同的CMR方案。结果随访时左室舒张末期容积(EDV)(158±29比143±29 mL, p = 0.013)和收缩期末期容积(ESV)(68±18比62±18 mL, p = 0.011)均低于对照组。相比之下,左室质量(LVM)(72±25 vs 82±29 g, p <;LVM/EDV比值(0.46±0.12比0.58±0.23 g/mL, p = 0.005)升高,T1时间延长(940±42比1010±35 ms, p <;0.001)。左室EF(57±6比57±7%,p = 0.90),纵向(GLS)和周向(GCS)收缩应变保持不变,但早期舒张血流动力学(HD)力更明显为负(- 19.4±7.0比- 26.5±12.2%,p = 0.012),而LA应变(43.8±11.3比37.3±9.6%,p = 0.031)和主动脉扩张(6.38±1.75比5.21±1.17 10−3 mmHg−1,p = 0.008)在随访中下降。与对照组相比,PKU患者的收缩期功能降低,左室EF降低,GCS受损,早期舒张期HD压明显为负。Phe浓度下降越高(ΔPhe), T1时间越长,ΔT1 (β = - 0.78, p <;0.001), ECV升高ΔECV (β = - 0.61, p = 0.016),收缩功能降低ΔEF (β = 0.61, p = 0.017)。相反,Tyr浓度的变化不影响心脏表型。结论在长期随访中,PKU患者血浆Phe浓度的显著下降与左室收缩功能下降和弥漫性纤维化增加等有害心脏重构相关。这些新数据提示进一步研究大Phe变异性随时间的影响,并强调对PKU成人患者进行定期心血管评估的有效性。
{"title":"Large Variations in Phenylalanine Concentrations Associate Adverse Cardiac Remodelling in Adult Patients With Phenylketonuria—A Long-Term CMR Study","authors":"Radu Tanacli,&nbsp;Patrick Doeblin,&nbsp;Alessandro Faragli,&nbsp;Jan-Hendrik Hassel,&nbsp;Christian Stehning,&nbsp;Ursula Plöckinger,&nbsp;Athanasia Ziagaki,&nbsp;Sebastian Kelle","doi":"10.1002/jcsm.13667","DOIUrl":"10.1002/jcsm.13667","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Despite a phenylalanine (Phe) restrictive diet, most adult patients with ‘classical’ phenylketonuria (PKU) maintain life-long Phe concentrations above the normal range and receive tyrosine (Tyr) and protein-enriched diets to maintain acceptable concentrations and ensure normal development. While these interventions are highly successful in preventing adverse neuropsychiatric complications, their long- term consequences are incompletely explored. We observed early cardiomyopathic characteristics and associated hemodynamic changes in adult PKU patients and present here the results of a longitudinal evaluation of cardiac phenotype.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Fifteen adult patients with PKU (age: 39.8 ± 8.1 years, 9 males and 6 females) underwent a comprehensive follow-up cardiac magnetic resonance (CMR) imaging assessment after a mean follow-up interval of 8.3 ± 0.3 years from the initial baseline visit. The CMR protocol included left (LV) and right (RV) ventricular and left atrial (LA) volumetric assessment, LV parametric mapping (precontrast and postcontrast T1 and T2 maps, extracellular volume [ECV]), multilayer LV myocardial strain, systolic and diastolic hemodynamic forces and RV and LA strain and aortic distensibility evaluation. Plasma concentrations of Phe, tyrosine (Tyr) and other biochemical markers of disease were retrospectively collected. For comparison, a group of 20 matched control subjects undergoing an identical CMR protocol was included.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;On average, the LV end-diastolic volume (EDV) (158 ± 29 vs. 143 ± 29 mL, &lt;i&gt;p&lt;/i&gt; = 0.013) and end-systolic volume (ESV) (68 ± 18 vs. 62 ± 18 mL, &lt;i&gt;p&lt;/i&gt; = 0.011) were lower at follow-up. In contrast, LV mass (LVM) (72 ± 25 vs. 82 ± 29 g, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and the ratio LVM/EDV (0.46 ± 0.12 vs. 0.58 ± 0.23 g/mL, &lt;i&gt;p&lt;/i&gt; = 0.005) were increased, and T1 times were longer (940 ± 42 vs. 1010 ± 35 ms, &lt;i&gt;p&lt;/i&gt; &lt; 0.001). LV EF (57 ± 6 vs. 57 ± 7%, &lt;i&gt;p&lt;/i&gt; = 0.90), longitudinal (GLS) and circumferential (GCS) systolic strain remained unchanged, but early diastolic hemodynamic (HD) forces were more markedly negative (−19.4 ± 7.0 vs. −26.5 ± 12.2%, &lt;i&gt;p&lt;/i&gt; = 0.012), while LA strain 43.8 ± 11.3 vs. 37.3 ± 9.6%, &lt;i&gt;p&lt;/i&gt; = 0.031) and aortic distensibility (6.38 ± 1.75 vs. 5.21 ± 1.17 10&lt;sup&gt;−3&lt;/sup&gt; mmHg&lt;sup&gt;−1&lt;/sup&gt;, &lt;i&gt;p&lt;/i&gt; = 0.008) decreased at follow-up. Compared with controls, PKU patients maintain reduced systolic function with lower LV EF and impaired GCS and have more markedly negative early diastolic HD pressures. A higher decrease in Phe concentration (ΔPhe) was associated with longer T1","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13667","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142961586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence 骨骼肌障碍在COVID后和肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)中的关键病理生理作用:积累证据
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-12-27 DOI: 10.1002/jcsm.13669
Carmen Scheibenbogen, Klaus J. Wirth
<div> <section> <h3> Background</h3> <p>Recent studies provide strong evidence for a key role of skeletal muscle pathophysiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In a 2021 review article on the pathophysiology of ME/CFS, we postulated that hypoperfusion and ischemia can result in excessive sodium and calcium overload in skeletal muscles of ME/CFS patients to cause mitochondrial damage. Since then, experimental evidence has been provided that supports this concept.</p> </section> <section> <h3> Methods</h3> <p>We collect, summarize and discuss the current state of knowledge for the key role of skeletal muscle pathophysiology. We try to explain which risk factors and mechanisms are responsible for a subgroup of patients with post COVID syndrome (PCS) to develop ME/CFS (PC-ME/CFS).</p> </section> <section> <h3> Results</h3> <p>Mitochondrial dysfunction is a long-held assumption to explain cardinal symptoms of ME/CFS. However, mitochondrial dysfunction could not be convincingly shown in leukocytes. By contrast, recent studies provide strong evidence for mitochondrial dysfunction in skeletal muscle tissue in ME/CFS. An electron microscopy study could directly show damage of mitochondria in skeletal muscle of ME/CFS patients with a preferential subsarcolemmal localization but not in PCS. Another study shows signs of skeletal muscle damage and regeneration in biopsies taken one day after exercise in PC-ME/CFS. The simultaneous presence of necroses and signs of regeneration supports the concept of repeated damage. Other studies correlated diminished hand grip strength (HGS) with symptom severity and prognosis. A MRI study showed that intracellular sodium in muscles of ME/CFS patients is elevated and that levels correlate inversely with HGS. This finding corroborates our concept of sodium and consecutive calcium overload as cause of muscular and mitochondrial damage caused by enhanced proton-sodium exchange due to anaerobic metabolism and diminished activity of the sodium-potassium-ATPase. The histological investigations in ME/CFS exclude ischemia by microvascular obstruction, viral presence or immune myositis. The only known exercise-induced mechanism of damage left is sodium induced calcium overload. If ionic disturbance and mitochondrial dysfunction is severe enough the patient may be captured in a vicious circle. This energy deficit is the most likely cause of exertional intolerance and post exertional malaise and is further aggravated by exertion.</p> </section> <section> <h3> Conclusion</h3> <p>Based on this pathomechani
最近的研究为骨骼肌病理生理在肌痛性脑脊髓炎/慢性疲劳综合征(ME/CFS)中的关键作用提供了强有力的证据。在2021年的一篇关于ME/CFS病理生理学的综述文章中,我们假设灌注不足和缺血可导致ME/CFS患者骨骼肌钠钙超载,从而导致线粒体损伤。从那以后,实验证据支持了这一概念。方法收集、总结和讨论骨骼肌病理生理的关键作用的现有知识。我们试图解释哪些危险因素和机制导致了一个亚组的后COVID综合征(PCS)患者发展为ME/CFS (PC‐ME/CFS)。结果长期以来,线粒体功能障碍被认为是ME/CFS主要症状的原因。然而,线粒体功能障碍不能令人信服地显示在白细胞。相比之下,最近的研究提供了强有力的证据,证明ME/CFS骨骼肌组织存在线粒体功能障碍。电镜研究可以直接显示ME/CFS患者骨骼肌线粒体的损伤,具有优先的肌下定位,而PCS没有。另一项研究显示,PC - ME/CFS患者运动后一天的活检显示骨骼肌损伤和再生的迹象。同时出现的坏死和再生的迹象支持了重复伤害的概念。其他研究将手部握力减弱(HGS)与症状严重程度和预后相关。一项MRI研究显示,ME/CFS患者肌肉细胞内钠升高,其水平与HGS呈负相关。这一发现证实了我们的概念,即钠和连续钙超载是由无氧代谢引起的质子-钠交换增强和钠-钾- atp酶活性降低引起的肌肉和线粒体损伤的原因。ME/CFS的组织学检查排除了微血管阻塞、病毒存在或免疫性肌炎引起的缺血。唯一已知的运动引起的损伤机制是钠诱导的钙超载。如果离子干扰和线粒体功能障碍足够严重,患者可能陷入恶性循环。这种能量不足是最可能导致运动不耐受和运动后不适的原因,并因运动而进一步恶化。结论基于这一病理机制,未来的治疗方法应侧重于使离子失衡的原因正常化。目前针对低灌注的治疗策略有可能改善离子转运体的功能障碍。
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引用次数: 0
Succinate Regulates Exercise-Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1 琥珀酸盐通过琥珀酸受体1促进卫星细胞分化,调节运动诱导的肌肉重塑
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-12-26 DOI: 10.1002/jcsm.13670
Yifan Shi, Da Zhou, Haoyang Wang, Longchang Huang, Xuejin Gao, Gulisudumu Maitiabula, Li Zhang, Xinying Wang
<div> <section> <h3> Background</h3> <p>Skeletal muscle remodelling can cause clinically important changes in muscle phenotypes. Satellite cells (SCs) myogenic potential underlies the maintenance of muscle plasticity. Accumulating evidence shows the importance of succinate in muscle metabolism and function. However, whether succinate can affect SC function and subsequently coordinate muscle remodelling to exercise remains unexplored.</p> </section> <section> <h3> Methods</h3> <p>A mouse model of high-intensity interval training (HIIT) was used to investigate the effects of succinate on muscle remodelling and SC function by exercise capacity test and biochemical methods. Mice with succinate receptor 1 (SUCNR1)-specific knockout in SCs were generated as an in vivo model to explore the underlying mechanisms. RNA sequencing of isolated SCs was performed to identify molecular changes responding to succinate-SUCNR1 signalling. The effects of identified key molecules on the myogenic capacity of SCs were investigated using gain- and loss-of-function assays in vitro. To support the translational application, the clinical efficacy of succinate was explored in muscle-wasting mice.</p> </section> <section> <h3> Results</h3> <p>After 21 days of HIIT, mice supplemented with 1.5% succinate exhibited striking gains in grip strength (+0.38 ± 0.04 vs. 0.26 ± 0.03 N, <i>p</i> < 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, <i>p</i> < 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (<i>p</i> < 0.001). The myogenic capacity of SCs was significantly increased in gastrocnemius muscle of mice supplemented with 1% and 1.5% succinate (+16.48% vs. control, <i>p</i> = 0.008; +47.25% vs. control, <i>p</i> < 0.001, respectively). SUCNR1-specific deletion in SCs abolished the modulatory influence of succinate on muscle adaptation in response to exercise, revealing that SCs respond to succinate–SUCNR1 signalling, thereby facilitating muscle remodelling. SUCNR1 signalling markedly upregulated genes associated with stem cell differentiation and phosphorylation pathways within SCs, of which p38α mitogen-activated protein kinase (MAPK; fold change = 6.7, <i>p</i> < 0.001) and protein kinase C eta (PKCη; fold change = 12.5, <i>p</i> < 0.001) expressions were the most enriched, respectively. Mechanistically, succinate enhanced the myogenic capacity of isolated SCs by activating the SUCNR1–PKCη–p38α MAPK pathway. Finally, succinate promoted SC differentiation (1.5-fold, <i>p</i> < 0.001), ameliorating dexamethasone-induced muscle atrophy in mice (<i>p</i> < 0.001).</p> </section>
背景骨骼肌重塑可引起临床上重要的肌肉表型变化。卫星细胞(SCs)的生肌潜能是维持肌肉可塑性的基础。越来越多的证据表明,琥珀酸盐在肌肉代谢和功能中具有重要作用。方法采用高强度间歇训练(HIIT)小鼠模型,通过运动能力测试和生化方法研究琥珀酸对肌肉重塑和SC功能的影响。为探索其潜在机制,小鼠体内的SC被琥珀酸受体1(SUCNR1)特异性敲除。对分离的SCs进行RNA测序,以确定响应琥珀酸-SUCNR1信号的分子变化。利用体外功能增益和功能缺失试验研究了已确定的关键分子对 SCs 成肌能力的影响。为了支持转化应用,我们在肌肉萎缩小鼠体内探索了琥珀酸盐的临床疗效。结果经过21天的HIIT后,补充1.5%琥珀酸盐的小鼠表现出惊人的握力增长(+0.38 ± 0.04 vs. 0.26 ± 0.03 N,p < 0.001)和耐力(+276.70 ± 55.80 vs. 201.70 ± 45.31 s,p < 0.05),同时肌肉肥大和神经肌肉接头再生增强(p < 0.001)。补充 1%和 1.5%琥珀酸盐的小鼠腓肠肌的 SCs 成肌能力显著提高(与对照组相比分别提高 16.48%,p = 0.008;与对照组相比分别提高 47.25%,p <0.001)。SCs中SUCNR1特异性缺失消除了琥珀酸对肌肉适应运动反应的调节影响,揭示了SCs对琥珀酸-SUCNR1信号的响应,从而促进了肌肉重塑。SUCNR1信号明显上调了SCs内与干细胞分化和磷酸化途径相关的基因,其中p38α丝裂原活化蛋白激酶(MAPK;折叠变化=6.7,p <;0.001)和蛋白激酶C eta(PKCη;折叠变化=12.5,p <;0.001)的表达分别最为丰富。从机制上看,琥珀酸盐通过激活SUCNR1-PKCη-p38α MAPK通路增强了离体SC的成肌能力。最后,琥珀酸盐促进了 SC 分化(1.5 倍,p <0.001),改善了地塞米松诱导的小鼠肌肉萎缩(p <0.001)。这些发现为开发克服肌肉萎缩相关疾病的药理策略提供了新的见解。
{"title":"Succinate Regulates Exercise-Induced Muscle Remodelling by Boosting Satellite Cell Differentiation Through Succinate Receptor 1","authors":"Yifan Shi,&nbsp;Da Zhou,&nbsp;Haoyang Wang,&nbsp;Longchang Huang,&nbsp;Xuejin Gao,&nbsp;Gulisudumu Maitiabula,&nbsp;Li Zhang,&nbsp;Xinying Wang","doi":"10.1002/jcsm.13670","DOIUrl":"10.1002/jcsm.13670","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Skeletal muscle remodelling can cause clinically important changes in muscle phenotypes. Satellite cells (SCs) myogenic potential underlies the maintenance of muscle plasticity. Accumulating evidence shows the importance of succinate in muscle metabolism and function. However, whether succinate can affect SC function and subsequently coordinate muscle remodelling to exercise remains unexplored.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A mouse model of high-intensity interval training (HIIT) was used to investigate the effects of succinate on muscle remodelling and SC function by exercise capacity test and biochemical methods. Mice with succinate receptor 1 (SUCNR1)-specific knockout in SCs were generated as an in vivo model to explore the underlying mechanisms. RNA sequencing of isolated SCs was performed to identify molecular changes responding to succinate-SUCNR1 signalling. The effects of identified key molecules on the myogenic capacity of SCs were investigated using gain- and loss-of-function assays in vitro. To support the translational application, the clinical efficacy of succinate was explored in muscle-wasting mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;After 21 days of HIIT, mice supplemented with 1.5% succinate exhibited striking gains in grip strength (+0.38 ± 0.04 vs. 0.26 ± 0.03 N, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and endurance (+276.70 ± 55.80 vs. 201.70 ± 45.31 s, &lt;i&gt;p&lt;/i&gt; &lt; 0.05), accompanied by enhanced muscle hypertrophy and neuromuscular junction regeneration (&lt;i&gt;p&lt;/i&gt; &lt; 0.001). The myogenic capacity of SCs was significantly increased in gastrocnemius muscle of mice supplemented with 1% and 1.5% succinate (+16.48% vs. control, &lt;i&gt;p&lt;/i&gt; = 0.008; +47.25% vs. control, &lt;i&gt;p&lt;/i&gt; &lt; 0.001, respectively). SUCNR1-specific deletion in SCs abolished the modulatory influence of succinate on muscle adaptation in response to exercise, revealing that SCs respond to succinate–SUCNR1 signalling, thereby facilitating muscle remodelling. SUCNR1 signalling markedly upregulated genes associated with stem cell differentiation and phosphorylation pathways within SCs, of which p38α mitogen-activated protein kinase (MAPK; fold change = 6.7, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) and protein kinase C eta (PKCη; fold change = 12.5, &lt;i&gt;p&lt;/i&gt; &lt; 0.001) expressions were the most enriched, respectively. Mechanistically, succinate enhanced the myogenic capacity of isolated SCs by activating the SUCNR1–PKCη–p38α MAPK pathway. Finally, succinate promoted SC differentiation (1.5-fold, &lt;i&gt;p&lt;/i&gt; &lt; 0.001), ameliorating dexamethasone-induced muscle atrophy in mice (&lt;i&gt;p&lt;/i&gt; &lt; 0.001).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000","PeriodicalId":48911,"journal":{"name":"Journal of Cachexia Sarcopenia and Muscle","volume":"16 1","pages":""},"PeriodicalIF":9.4,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcsm.13670","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Intrinsic Muscle Stem Cell Dysfunction Contributes to Impaired Regeneration in the mdx Mouse 内在肌肉干细胞功能障碍导致mdx小鼠再生受损
IF 9.4 1区 医学 Q1 GERIATRICS & GERONTOLOGY Pub Date : 2024-12-26 DOI: 10.1002/jcsm.13682
Marie E. Esper, Caroline E. Brun, Alexander Y. T. Lin, Peter Feige, Marie J. Catenacci, Marie-Claude Sincennes, Morten Ritso, Michael A. Rudnicki
<div> <section> <h3> Background</h3> <p>Duchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting that leads to diminished lifespan. In addition to the inherent weakness of dystrophin-deficient muscle, the dysfunction of resident muscle stem cells (MuSC) significantly contributes to disease progression.</p> </section> <section> <h3> Methods</h3> <p>Using the <i>mdx</i> mouse model of DMD, we performed an in-depth characterization of disease progression and MuSC function in dystrophin-deficient skeletal muscle using immunohistology, isometric force measurements, transcriptomic analysis and transplantation assays. We examined the architectural and functional changes in <i>mdx</i> skeletal muscle from 13 and 52 weeks of age and following acute cardiotoxin (CTX) injury. We also studied MuSC dynamics and function under homeostatic conditions, during regeneration post-acute injury, and following engraftment using a combination of histological and transcriptomic analyses.</p> </section> <section> <h3> Results</h3> <p>Dystrophin-deficient skeletal muscle undergoes progressive changes with age and delayed regeneration in response to acute injury. Muscle hypertrophy, deposition of collagen and an increase in small myofibres occur with age in the <i>tibialis anterior</i> (TA) and diaphragm muscles in <i>mdx</i> mice. Dystrophic <i>mdx</i> mouse TA muscles become hypertrophic with age, whereas diaphragm atrophy is evident in 1-year-old <i>mdx</i> mice. Maximum tetanic force is comparable between genotypes in the TA, but maximum specific force is reduced by up to 38% between 13 and 52 weeks in the <i>mdx</i> mouse. Following acute injury, myofibre hyperplasia and hypotrophy and delayed recovery of maximum tetanic force occur in the <i>mdx</i> TA. We also find defective MuSC polarity and reduced numbers of myocytes in <i>mdx</i> muscle following acute injury. We observed a 50% and 30% decrease in PAX7<sup>+</sup> and MYOG<sup>+</sup> cells, respectively, at 5 days post CTX injury (5 dpi) in the <i>mdx</i> TA. A similar decrease in <i>mdx</i> progenitor cell proportion is observed by single cell RNA sequencing of myogenic cells at 5 dpi. The global expression of commitment-related genes is also reduced at 5 dpi. We find a 46% reduction in polarized PARD3 in <i>mdx</i> MuSCs. Finally, <i>mdx</i> MuSCs exhibit elevated PAX7<sup>+</sup> cell engraftment with significantly fewer donor-derived myonuclei in regenerated myofibres.</p> </section> <section> <h3> Conclusions</h3> <p>Our study provides evidence that dystrophin de
背景杜氏肌营养不良症(DMD)是一种破坏性疾病,其特点是进行性肌肉萎缩,导致寿命缩短。方法我们利用 mdx DMD 小鼠模型,通过免疫组织学、等力测量、转录组分析和移植试验,对淀粉样蛋白缺陷骨骼肌的疾病进展和 MuSC 功能进行了深入研究。我们研究了mdx骨骼肌在13周龄和52周龄以及急性心脏毒素(CTX)损伤后的结构和功能变化。我们还使用组织学和转录组分析相结合的方法,研究了MuSC在平衡条件下、急性损伤后再生期间以及移植后的动态和功能。随着年龄的增长,mdx 小鼠的胫骨前肌(TA)和膈肌会出现肌肉肥大、胶原沉积和小肌纤维增加。萎缩性 mdx 小鼠的胫骨前肌(TA)和膈肌会随着年龄的增长而变得肥厚,而 1 岁的 mdx 小鼠则会出现明显的膈肌萎缩。不同基因型小鼠TA肌肉的最大张力相当,但在13至52周期间,mdx小鼠的最大比张力降低了38%。急性损伤后,mdx TA 的肌纤维增生和萎缩,以及最大肌张力恢复延迟。我们还发现,急性损伤后,mdx肌肉中的MuSC极性缺陷和肌细胞数量减少。我们观察到,在 CTX 损伤后 5 天(5 dpi),mdx TA 中 PAX7+ 和 MYOG+ 细胞分别减少了 50%和 30%。在 5 dpi 时,通过对肌原细胞进行单细胞 RNA 测序,我们也观察到 mdx 祖细胞比例出现了类似的下降。在 5 dpi 时,承诺相关基因的整体表达也有所减少。我们发现,mdx MuSCs 中极化的 PARD3 减少了 46%。最后,mdx MuSCs 表现出较高的 PAX7+ 细胞移植性,再生肌纤维中的供体衍生肌核明显减少。结论我们的研究提供了证据,证明 MuSCs 和肌纤维中的肌营养不良素缺乏共同导致了 DMD 的进展。持续的肌肉损伤会刺激间充质干细胞的活化;然而,由于肌营养不良蛋白的缺失,间充质干细胞固有极性的异常和干细胞承诺的缺失会损害肌肉再生。我们的研究在体内验证了缺乏肌营养不良蛋白的肌肉干细胞进行较少的非对称细胞分裂,而是倾向于对称性扩张。
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引用次数: 0
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Journal of Cachexia Sarcopenia and Muscle
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