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Limb-girdle muscular dystrophy type 2B causes HDL-C abnormalities in patients and statin-resistant muscle wasting in dysferlin-deficient mice. 2B型肢带性肌营养不良症导致患者HDL-C异常,并导致异ferlin缺乏小鼠出现他汀类药物抵抗性肌肉萎缩。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-11-29 DOI: 10.1186/s13395-022-00308-6
Zoe White, Zeren Sun, Elodie Sauge, Dan Cox, Graham Donen, Dmitri Pechkovsky, Volker Straub, Gordon A Francis, Pascal Bernatchez

Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage. Herein, lipoproteins and liver enzymes from LGMD2B patients and dysferlin-null (Dysf) mice were analyzed. Simvastatin, which exhibits anti-muscle wasting effects in mouse models of DMD and corrects aberrant expression of key markers of lipid metabolism and endogenous cholesterol synthesis, was tested in Dysf mice. Muscle damage and fibrosis were assessed by immunohistochemistry and cholesterol signalling pathways via Western blot. LGMD2B patients show reduced serum high-density lipoprotein cholesterol (HDL-C) levels compared to healthy controls and exhibit a greater prevalence of abnormal total cholesterol (CHOL)/HDL-C ratios despite an absence of liver dysfunction. While Dysf mice presented with reduced CHOL and associated HDL-C and LDL-C-associated fractions, simvastatin treatment did not prevent muscle wasting in quadriceps and triceps muscle groups or correct aberrant low-density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) protein expression. LGMD2B patients present with reduced serum concentrations of HDL-C, a major metabolic comorbidity, and as a result, statin therapy is unlikely to prevent muscle wasting in this population. We propose that like DMD, LGMD2B should be considered as a new type of genetic dyslipidemia.

四肢带状肌营养不良(MD) 2B型(LGMD2B)和杜氏肌营养不良(DMD)分别是由Dysferlin和Dystrophin基因突变引起的。我们最近在典型的轻度dysferlin和dystrophin缺陷小鼠模型中证明,血浆胆固醇水平升高严重加剧了肌肉萎缩,DMD患者表现出以血浆胆固醇和甘油三酯升高为特征的原发性血脂异常。在这里,我们研究了LGMD2B的脂蛋白异常,以及他汀类药物治疗是否能保护dysferlin缺陷小鼠(Dysf)免受肌肉损伤。本文对LGMD2B患者和dysferlin-null (Dysf)小鼠的脂蛋白和肝酶进行分析。辛伐他汀在DMD小鼠模型中表现出抗肌肉萎缩作用,并纠正脂质代谢和内源性胆固醇合成关键标志物的异常表达,在Dysf小鼠中进行了测试。通过免疫组化和Western blot检测胆固醇信号通路评估肌肉损伤和纤维化。与健康对照相比,LGMD2B患者血清高密度脂蛋白胆固醇(HDL-C)水平降低,尽管没有肝功能障碍,但总胆固醇(CHOL)/HDL-C比率异常的发生率更高。虽然Dysf小鼠表现出CHOL和相关HDL-C和ldl - c相关部分的降低,但辛伐他汀治疗并不能防止股四头肌和三头肌肌肉群的肌肉萎缩,也不能纠正低密度脂蛋白受体(LDLR)和3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)蛋白表达的异常。LGMD2B患者表现为血清HDL-C浓度降低,这是一种主要的代谢合并症,因此,他汀类药物治疗不太可能预防该人群的肌肉萎缩。我们建议与DMD一样,将LGMD2B视为一种新型的遗传性血脂异常。
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引用次数: 3
Macroglossia and less advanced dystrophic change in the tongue muscle of the Duchenne muscular dystrophy rat. 杜氏肌营养不良大鼠舌肌大舌失音及不太严重的营养不良改变。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-10-19 DOI: 10.1186/s13395-022-00307-7
Keitaro Yamanouchi, Yukie Tanaka, Masanari Ikeda, Shizuka Kato, Ryosuke Okino, Hiroki Nishi, Fumihiko Hakuno, Shin-Ichiro Takahashi, James Chambers, Takashi Matsuwaki, Kazuyuki Uchida

Background: Duchenne muscular dystrophy (DMD) is an X-linked muscle disease caused by a complete lack of dystrophin, which stabilizes the plasma membrane of myofibers. The orofacial function is affected in an advanced stage of DMD and this often leads to an eating disorder such as dysphagia. Dysphagia is caused by multiple etiologies including decreased mastication and swallowing. Therefore, preventing the functional declines of mastication and swallowing in DMD is important to improve the patient's quality of life. In the present study, using a rat model of DMD we generated previously, we performed analyses on the masseter and tongue muscles, both are required for proper eating function.

Methods: Age-related changes of the masseter and tongue muscle of DMD rats were analyzed morphometrically, histologically, and immunohistochemically. Also, transcription of cellular senescent markers, and utrophin (Utrn), a functional analog of dystrophin, was examined.

Results: The masseter muscle of DMD rats showed progressive dystrophic changes as observed in their hindlimb muscle, accompanied by increased transcription of p16 and p19. On the other hand, the tongue of DMD rats showed macroglossia due to hypertrophy of myofibers with less dystrophic changes. Proliferative activity was preserved in the satellite cells from the tongue muscle but was perturbed severely in those from the masseter muscle. While Utrn transcription was increased in the masseter muscle of DMD rats compared to WT rats, probably due to a compensatory mechanism, its level in the tongue muscle was comparable between WT and DMD rats and was similar to that in the masseter muscle of DMD rats.

Conclusions: Muscular dystrophy is less advanced in the tongue muscle compared to the masseter muscle in the DMD rat.

背景:杜氏肌营养不良症(DMD)是一种由完全缺乏肌营养不良蛋白引起的x连锁肌肉疾病,肌营养不良蛋白可以稳定肌纤维的质膜。口腔面部功能在DMD的晚期阶段受到影响,这通常会导致进食障碍,如吞咽困难。吞咽困难是由多种病因引起的,包括咀嚼和吞咽减少。因此,预防DMD患者咀嚼和吞咽功能下降对提高患者的生活质量具有重要意义。在本研究中,我们使用之前制作的大鼠DMD模型,对咬肌和舌肌进行了分析,这两个肌肉都是正常进食功能所必需的。方法:对DMD大鼠咬肌和舌肌的年龄相关性变化进行形态学、组织学和免疫组织化学分析。此外,我们还研究了细胞衰老标记物和肌营养不良蛋白的功能类似物——肌营养不良蛋白(Utrn)的转录。结果:DMD大鼠咬肌后肢肌出现进行性营养不良改变,p16、p19转录增加。另一方面,DMD大鼠的舌头由于肌纤维肥大而出现大舌语,营养不良改变较少。舌肌卫星细胞的增殖活性保持不变,而咬肌卫星细胞的增殖活性受到严重干扰。虽然与WT大鼠相比,DMD大鼠咬肌中的Utrn转录增加,可能是一种代偿机制,但其在舌肌中的水平在WT和DMD大鼠之间是相当的,与DMD大鼠咬肌中的水平相似。结论:与DMD大鼠的咬肌相比,舌肌的肌肉萎缩程度较轻。
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引用次数: 2
Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review. 由CHKB变异引起的巨头先天性肌营养不良:1例报告及文献复习。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-09-29 DOI: 10.1186/s13395-022-00306-8
Francesca Magri, Sara Antognozzi, Michela Ripolone, Simona Zanotti, Laura Napoli, Patrizia Ciscato, Daniele Velardo, Giulietta Scuvera, Valeria Nicotra, Antonella Giacobbe, Donatella Milani, Francesco Fortunato, Manuela Garbellini, Monica Sciacco, Stefania Corti, Giacomo Pietro Comi, Dario Ronchi

Background: Choline kinase beta (CHKB) catalyzes the first step in the de novo biosynthesis of phosphatidyl choline and phosphatidylethanolamine via the Kennedy pathway. Derangement of this pathway might also influence the homeostasis of mitochondrial membranes. Autosomal recessive CHKB mutations cause a rare form of congenital muscular dystrophy known as megaconial congenital muscular dystrophy (MCMD).

Case presentation: We describe a novel proband presenting MCMD due to unpublished CHKB mutations. The patient is a 6-year-old boy who came to our attention for cognitive impairment and slowly progressive muscular weakness. He was the first son of non-consanguineous healthy parents from Sri Lanka. Neurological examination showed proximal weakness at four limbs, weak osteotendinous reflexes, Gowers' maneuver, and waddling gate. Creatine kinase levels were mildly increased. EMG and brain MRI were normal. Left quadriceps skeletal muscle biopsy showed a myopathic pattern with nuclear centralizations and connective tissue increase. Histological and histochemical staining suggested subsarcolemmal localization and dimensional increase of mitochondria. Ultrastructural analysis confirmed the presence of enlarged ("megaconial") mitochondria. Direct sequencing of CHKB identified two novel defects: the c.1060G > C (p.Gly354Arg) substitution and the c.448-56_29del intronic deletion, segregating from father and mother, respectively. Subcloning of RT-PCR amplicons from patient's muscle RNA showed that c.448-56_29del results in the partial retention (14 nucleotides) of intron 3, altering physiological splicing and transcript stability. Biochemical studies showed reduced levels of the mitochondrial fission factor DRP1 and the severe impairment of mitochondrial respiratory chain activity in patient's muscle compared to controls.

Conclusions: This report expands the molecular findings associated with MCMD and confirms the importance of considering CHKB variants in the differential diagnosis of patients presenting with muscular dystrophy and mental retardation. The clinical outcome of MCMD patients seems to be influenced by CHKB molecular defects. Histological and ultrastructural examination of muscle biopsy directed molecular studies and allowed the identification and characterization of an intronic mutation, usually escaping standard molecular testing.

背景:胆碱激酶β (CHKB)通过肯尼迪途径催化磷脂酰胆碱和磷脂酰乙醇胺从头合成的第一步。该通路的紊乱也可能影响线粒体膜的稳态。常染色体隐性CHKB突变导致一种罕见的先天性肌肉萎缩症,称为巨头先天性肌肉萎缩症(MCMD)。病例介绍:我们描述了一个新的先证者由于未发表的CHKB突变而呈现MCMD。患者是一名6岁男孩因认知障碍和缓慢进行性肌肉无力而入院。他是来自斯里兰卡的非近亲健康父母的长子。神经学检查显示四肢近端无力,骨腱反射弱,高尔斯运动和蹒跚门。肌酸激酶水平轻度升高。肌电图和脑MRI正常。左股四头肌骨骼肌活检显示肌病模式,核集中和结缔组织增加。组织学和组织化学染色显示线粒体在肌层下定位,尺寸增大。超微结构分析证实线粒体增大(“巨头”)。CHKB的直接测序发现了两个新的缺陷:C . 1060g > C (p.Gly354Arg)取代和C .448-56_29del内含子缺失,分别来自父亲和母亲。从患者肌肉RNA中提取的RT-PCR扩增子亚克隆表明,c.448-56_29del导致内含子3的部分保留(14个核苷酸),改变了生理剪接和转录物的稳定性。生化研究显示,与对照组相比,患者肌肉中线粒体裂变因子DRP1水平降低,线粒体呼吸链活性严重受损。结论:本报告扩展了与MCMD相关的分子发现,并证实了考虑CHKB变异在肌肉萎缩症和智力低下患者鉴别诊断中的重要性。MCMD患者的临床预后似乎受到CHKB分子缺陷的影响。肌肉活检的组织学和超微结构检查指导分子研究,并允许识别和表征内含子突变,通常逃避标准的分子检测。
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引用次数: 1
Mouse models of SMA show divergent patterns of neuronal vulnerability and resilience. 小鼠SMA模型显示出不同的神经元脆弱性和弹性模式。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-09-12 DOI: 10.1186/s13395-022-00305-9
Victoria Woschitz, Irene Mei, Eva Hedlund, Lyndsay M Murray

Background: Spinal muscular atrophy (SMA) is a form of motor neuron disease affecting primarily children characterised by the loss of lower motor neurons (MNs). Breakdown of the neuromuscular junctions (NMJs) is an early pathological event in SMA. However, not all motor neurons are equally vulnerable, with some populations being lost early in the disease while others remain intact at the disease end-stage. A thorough understanding of the basis of this selective vulnerability will give critical insight into the factors which prohibit pathology in certain motor neuron populations and consequently help identify novel neuroprotective strategies.

Methods: To retrieve a comprehensive understanding of motor neuron susceptibility in SMA, we mapped NMJ pathology in 20 muscles from the Smn2B/- SMA mouse model and cross-compared these data with published data from three other commonly used mouse models. To gain insight into the molecular mechanisms regulating selective resilience and vulnerability, we analysed published RNA sequencing data acquired from differentially vulnerable motor neurons from two different SMA mouse models.

Results: In the Smn2B/- mouse model of SMA, we identified substantial NMJ loss in the muscles from the core, neck, proximal hind limbs and proximal forelimbs, with a marked reduction in denervation in the distal limbs and head. Motor neuron cell body loss was greater at T5 and T11 compared with L5. We subsequently show that although widespread denervation is observed in each SMA mouse model (with the notable exception of the Taiwanese model), all models have a distinct pattern of selective vulnerability. A comparison of previously published data sets reveals novel transcripts upregulated with a disease in selectively resistant motor neurons, including genes involved in axonal transport, RNA processing and mitochondrial bioenergetics.

Conclusions: Our work demonstrates that the Smn2B/- mouse model shows a pattern of selective vulnerability which bears resemblance to the regional pathology observed in SMA patients. We found drastic differences in patterns of selective vulnerability across the four SMA mouse models, which is critical to consider during experimental design. We also identified transcript groups that potentially contribute to the protection of certain motor neurons in SMA mouse models.

背景:脊髓性肌萎缩症(SMA)是一种主要影响儿童的运动神经元疾病,其特征是下部运动神经元(MNs)的丧失。神经肌肉连接处的破坏是SMA的早期病理事件。然而,并非所有的运动神经元都同样脆弱,一些人在疾病早期就失去了运动神经元,而另一些人在疾病晚期仍然完好无损。彻底了解这种选择性易感性的基础将有助于深入了解某些运动神经元群体中禁止病理的因素,从而有助于确定新的神经保护策略。方法:为了全面了解SMA中运动神经元的易感性,我们绘制了Smn2B/- SMA小鼠模型中20块肌肉的NMJ病理图谱,并将这些数据与其他三种常用小鼠模型的已发表数据进行了交叉比较。为了深入了解调节选择性弹性和易损性的分子机制,我们分析了从两种不同SMA小鼠模型中获得的不同易损性运动神经元的RNA测序数据。结果:在Smn2B/-小鼠SMA模型中,我们发现核心、颈部、后肢近端和前肢近端肌肉的NMJ明显减少,远端肢体和头部的去神经支配明显减少。运动神经元胞体损失在T5和T11较L5大。我们随后表明,尽管在每个SMA小鼠模型中都观察到广泛的去神经支配(台湾模型除外),但所有模型都具有明显的选择性易损性模式。对先前发表的数据集的比较显示,在选择性抵抗运动神经元中,包括参与轴突运输、RNA加工和线粒体生物能量学的基因,新的转录本随着疾病而上调。结论:我们的工作表明,Smn2B/-小鼠模型显示出一种选择性易感性模式,这与SMA患者中观察到的区域病理相似。我们发现,在四种SMA小鼠模型中,选择性脆弱性的模式存在巨大差异,这在实验设计中是至关重要的。我们还确定了在SMA小鼠模型中可能有助于保护某些运动神经元的转录组。
{"title":"Mouse models of SMA show divergent patterns of neuronal vulnerability and resilience.","authors":"Victoria Woschitz,&nbsp;Irene Mei,&nbsp;Eva Hedlund,&nbsp;Lyndsay M Murray","doi":"10.1186/s13395-022-00305-9","DOIUrl":"https://doi.org/10.1186/s13395-022-00305-9","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a form of motor neuron disease affecting primarily children characterised by the loss of lower motor neurons (MNs). Breakdown of the neuromuscular junctions (NMJs) is an early pathological event in SMA. However, not all motor neurons are equally vulnerable, with some populations being lost early in the disease while others remain intact at the disease end-stage. A thorough understanding of the basis of this selective vulnerability will give critical insight into the factors which prohibit pathology in certain motor neuron populations and consequently help identify novel neuroprotective strategies.</p><p><strong>Methods: </strong>To retrieve a comprehensive understanding of motor neuron susceptibility in SMA, we mapped NMJ pathology in 20 muscles from the Smn<sup>2B/-</sup> SMA mouse model and cross-compared these data with published data from three other commonly used mouse models. To gain insight into the molecular mechanisms regulating selective resilience and vulnerability, we analysed published RNA sequencing data acquired from differentially vulnerable motor neurons from two different SMA mouse models.</p><p><strong>Results: </strong>In the Smn<sup>2B/-</sup> mouse model of SMA, we identified substantial NMJ loss in the muscles from the core, neck, proximal hind limbs and proximal forelimbs, with a marked reduction in denervation in the distal limbs and head. Motor neuron cell body loss was greater at T5 and T11 compared with L5. We subsequently show that although widespread denervation is observed in each SMA mouse model (with the notable exception of the Taiwanese model), all models have a distinct pattern of selective vulnerability. A comparison of previously published data sets reveals novel transcripts upregulated with a disease in selectively resistant motor neurons, including genes involved in axonal transport, RNA processing and mitochondrial bioenergetics.</p><p><strong>Conclusions: </strong>Our work demonstrates that the Smn<sup>2B/-</sup> mouse model shows a pattern of selective vulnerability which bears resemblance to the regional pathology observed in SMA patients. We found drastic differences in patterns of selective vulnerability across the four SMA mouse models, which is critical to consider during experimental design. We also identified transcript groups that potentially contribute to the protection of certain motor neurons in SMA mouse models.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9465884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33464624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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: 4
Identification of the co-differentially expressed hub genes involved in the endogenous protective mechanism against ventilator-induced diaphragm dysfunction. 鉴定参与呼吸机诱导膈肌功能障碍内源性保护机制的共差异表达枢纽基因。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-09-09 DOI: 10.1186/s13395-022-00304-w
Dong Zhang, Wenyan Hao, Qi Niu, Dongdong Xu, Xuejiao Duan

Background: In intensive care units (ICU), mechanical ventilation (MV) is commonly applied to save patients' lives. However, ventilator-induced diaphragm dysfunction (VIDD) can complicate treatment by hindering weaning in critically ill patients and worsening outcomes. The goal of this study was to identify potential genes involved in the endogenous protective mechanism against VIDD.

Methods: Twelve adult male rabbits were assigned to either an MV group or a control group under the same anesthetic conditions. Immunostaining and quantitative morphometry were used to assess diaphragm atrophy, while RNA-seq was used to investigate molecular differences between the groups. Additionally, core module and hub genes were analyzed using WGCNA, and co-differentially expressed hub genes were subsequently discovered by overlapping the differentially expressed genes (DEGs) with the hub genes from WGCNA. The identified genes were validated by western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR).

Results: After a VIDD model was successfully built, 1276 DEGs were found between the MV and control groups. The turquoise and yellow modules were identified as the core modules, and Trim63, Fbxo32, Uchl1, Tmprss13, and Cst3 were identified as the five co-differentially expressed hub genes. After the two atrophy-related genes (Trim63 and Fbxo32) were excluded, the levels of the remaining three genes/proteins (Uchl1/UCHL1, Tmprss13/TMPRSS13, and Cst3/CST3) were found to be significantly elevated in the MV group (P < 0.05), suggesting the existence of a potential antiproteasomal, antiapoptotic, and antiautophagic mechanism against diaphragm dysfunction.

Conclusion: The current research helps to reveal a potentially important endogenous protective mechanism that could serve as a novel therapeutic target against VIDD.

背景:在重症监护病房(ICU),机械通气(MV)是常用的挽救患者生命的手段。然而,呼吸机诱发的隔膜功能障碍(VIDD)会阻碍危重患者的脱机并恶化预后,从而使治疗复杂化。本研究的目的是确定参与内源性抗VIDD保护机制的潜在基因。方法:选取成年雄性家兔12只,在相同麻醉条件下分为MV组和对照组。采用免疫染色和定量形态测定法评估膈肌萎缩,采用RNA-seq法研究各组间的分子差异。此外,使用WGCNA分析核心模块和枢纽基因,随后通过将差异表达基因(deg)与WGCNA中的枢纽基因重叠,发现了共差异表达的枢纽基因。经western blotting (WB)和定量实时聚合酶链反应(qRT-PCR)验证所鉴定的基因。结果:成功建立VIDD模型后,MV组与对照组之间差异1276个deg。绿松石色和黄色模块被鉴定为核心模块,Trim63、Fbxo32、Uchl1、Tmprss13和Cst3被鉴定为5个共差异表达的枢纽基因。在排除这两个萎缩相关基因(Trim63和Fbxo32)后,其余3个基因/蛋白(Uchl1/ Uchl1、Tmprss13/ Tmprss13、Cst3/ Cst3)在MV组中表达水平显著升高(P < 0.05),提示膈肌功能障碍存在潜在的抗蛋白酶体、抗凋亡和抗自噬机制。结论:本研究有助于揭示一种潜在的重要内源性保护机制,该机制可能作为治疗VIDD的新靶点。
{"title":"Identification of the co-differentially expressed hub genes involved in the endogenous protective mechanism against ventilator-induced diaphragm dysfunction.","authors":"Dong Zhang,&nbsp;Wenyan Hao,&nbsp;Qi Niu,&nbsp;Dongdong Xu,&nbsp;Xuejiao Duan","doi":"10.1186/s13395-022-00304-w","DOIUrl":"https://doi.org/10.1186/s13395-022-00304-w","url":null,"abstract":"<p><strong>Background: </strong>In intensive care units (ICU), mechanical ventilation (MV) is commonly applied to save patients' lives. However, ventilator-induced diaphragm dysfunction (VIDD) can complicate treatment by hindering weaning in critically ill patients and worsening outcomes. The goal of this study was to identify potential genes involved in the endogenous protective mechanism against VIDD.</p><p><strong>Methods: </strong>Twelve adult male rabbits were assigned to either an MV group or a control group under the same anesthetic conditions. Immunostaining and quantitative morphometry were used to assess diaphragm atrophy, while RNA-seq was used to investigate molecular differences between the groups. Additionally, core module and hub genes were analyzed using WGCNA, and co-differentially expressed hub genes were subsequently discovered by overlapping the differentially expressed genes (DEGs) with the hub genes from WGCNA. The identified genes were validated by western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR).</p><p><strong>Results: </strong>After a VIDD model was successfully built, 1276 DEGs were found between the MV and control groups. The turquoise and yellow modules were identified as the core modules, and Trim63, Fbxo32, Uchl1, Tmprss13, and Cst3 were identified as the five co-differentially expressed hub genes. After the two atrophy-related genes (Trim63 and Fbxo32) were excluded, the levels of the remaining three genes/proteins (Uchl1/UCHL1, Tmprss13/TMPRSS13, and Cst3/CST3) were found to be significantly elevated in the MV group (P < 0.05), suggesting the existence of a potential antiproteasomal, antiapoptotic, and antiautophagic mechanism against diaphragm dysfunction.</p><p><strong>Conclusion: </strong>The current research helps to reveal a potentially important endogenous protective mechanism that could serve as a novel therapeutic target against VIDD.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9461262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33460739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells. 长时间的 FOS 活性通过改变原生肌肉祖细胞的三维染色质结构,破坏了全局性的成肌转录程序。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-08-15 DOI: 10.1186/s13395-022-00303-x
A Rasim Barutcu, Gabriel Elizalde, Alfredo E Gonzalez, Kartik Soni, John L Rinn, Amy J Wagers, Albert E Almada

Background: The AP-1 transcription factor, FBJ osteosarcoma oncogene (FOS), is induced in adult muscle satellite cells (SCs) within hours following muscle damage and is required for effective stem cell activation and muscle repair. However, why FOS is rapidly downregulated before SCs enter cell cycle as progenitor cells (i.e., transiently expressed) remains unclear. Further, whether boosting FOS levels in the proliferating progeny of SCs can enhance their myogenic properties needs further evaluation.

Methods: We established an inducible, FOS expression system to evaluate the impact of persistent FOS activity in muscle progenitor cells ex vivo. We performed various assays to measure cellular proliferation and differentiation, as well as uncover changes in RNA levels and three-dimensional (3D) chromatin interactions.

Results: Persistent FOS activity in primary muscle progenitor cells severely antagonizes their ability to differentiate and form myotubes within the first 2 weeks in culture. RNA-seq analysis revealed that ectopic FOS activity in muscle progenitor cells suppressed a global pro-myogenic transcriptional program, while activating a stress-induced, mitogen-activated protein kinase (MAPK) transcriptional signature. Additionally, we observed various FOS-dependent, chromosomal re-organization events in A/B compartments, topologically associated domains (TADs), and genomic loops near FOS-regulated genes.

Conclusions: Our results suggest that elevated FOS activity in recently activated muscle progenitor cells perturbs cellular differentiation by altering the 3D chromosome organization near critical pro-myogenic genes. This work highlights the crucial importance of tightly controlling FOS expression in the muscle lineage and suggests that in states of chronic stress or disease, persistent FOS activity in muscle precursor cells may disrupt the muscle-forming process.

背景:AP-1转录因子FBJ骨肉瘤癌基因(FOS)在肌肉损伤后数小时内就会在成肌卫星细胞(SCs)中被诱导,是干细胞有效激活和肌肉修复所必需的。然而,为什么FOS会在SCs作为祖细胞进入细胞周期之前迅速下调(即瞬时表达),目前仍不清楚。此外,提高 SCs 增殖祖细胞中的 FOS 水平是否能增强其致肌特性还需要进一步评估:我们建立了一个可诱导的 FOS 表达系统,以评估 FOS 在体内外肌肉祖细胞中持续活性的影响。我们进行了各种实验来测量细胞的增殖和分化,并揭示了 RNA 水平和三维染色质相互作用的变化:结果:原代肌肉祖细胞中持续存在的 FOS 活性严重影响了它们在培养头两周内分化和形成肌管的能力。RNA-seq分析显示,肌肉祖细胞中异位的FOS活性抑制了全局性的促肌肉生成转录程序,同时激活了应激诱导的丝裂原活化蛋白激酶(MAPK)转录特征。此外,我们还观察到 FOS 调控基因附近的 A/B 区、拓扑相关域(TAD)和基因组环路中发生了各种依赖 FOS 的染色体重组事件:我们的研究结果表明,最近激活的肌肉祖细胞中升高的 FOS 活性会通过改变关键的促肌肉生成基因附近的三维染色体组织来扰乱细胞分化。这项工作强调了严格控制 FOS 在肌肉系中表达的重要性,并表明在慢性应激或疾病状态下,肌肉前体细胞中持续的 FOS 活性可能会破坏肌肉形成过程。
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引用次数: 0
Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction. 氧化应激通过调节progerin-p53相互作用诱导过早衰老和加剧失神经骨骼肌萎缩。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-07-29 DOI: 10.1186/s13395-022-00302-y
Yaoxian Xiang, Zongqi You, Xinying Huang, Junxi Dai, Junpeng Zhang, Shuqi Nie, Lei Xu, Junjian Jiang, Jianguang Xu

Background: Progerin elevates atrophic gene expression and helps modify the nuclear membrane to cause severe muscle pathology, which is similar to muscle weakness in the elderly, to alter the development and function of the skeletal muscles. Stress-induced premature senescence (SIPS), a state of cell growth arrest owing to such stimuli as oxidation, can be caused by progerin. However, evidence for whether SIPS-induced progerin accumulation is connected to denervation-induced muscle atrophy is not sufficient.

Methods: Flow cytometry and a reactive oxygen species (ROS) as well as inducible nitric oxide synthase (iNOS) inhibitors were used to assess the effect of oxidation on protein (p53), progerin, and nuclear progerin-p53 interaction in the denervated muscles of models of mice suffering from sciatic injury. Loss-of-function approach with the targeted deletion of p53 was used to assess connection among SIPS, denervated muscle atrophy, and fibrogenesis.

Results: The augmentation of ROS and iNOS-derived NO in the denervated muscles of models of mice suffering from sciatic injury upregulates p53 and progerin. The abnormal accumulation of progerin in the nuclear membrane as well as the activation of nuclear progerin-p53 interaction triggered premature senescence in the denervated muscle cells of mice. The p53-dependent SIPS in denervated muscles contributes to their atrophy and fibrogenesis.

Conclusion: Oxidative stress-triggered premature senescence via nuclear progerin-p53 interaction that promotes denervated skeletal muscular atrophy and fibrogenesis.

背景:Progerin提高萎缩性基因表达,帮助修饰核膜,引起严重的肌肉病理,类似于老年人的肌肉无力,从而改变骨骼肌的发育和功能。应激性早衰(SIPS)是由于氧化等刺激导致细胞生长停滞的一种状态,可由progerin引起。然而,关于sips诱导的早衰蛋白积累是否与去神经支配诱导的肌肉萎缩有关的证据并不充分。方法:采用流式细胞术、活性氧(ROS)和诱导型一氧化氮合酶(iNOS)抑制剂检测氧化对坐骨神经损伤小鼠去神经支配肌肉中蛋白(p53)、早衰蛋白(progerin)和核早衰蛋白-p53相互作用的影响。p53靶向缺失的功能丧失方法被用于评估SIPS、失神经肌肉萎缩和纤维发生之间的联系。结果:坐骨损伤小鼠模型失神经肌肉中ROS和inos来源NO的增加可上调p53和progerin。核膜中早衰蛋白的异常积累以及核中早衰蛋白-p53相互作用的激活,导致小鼠失神经肌肉细胞过早衰老。去神经支配肌肉中p53依赖的SIPS有助于其萎缩和纤维形成。结论:氧化应激通过核progerin-p53相互作用引发过早衰老,促进失神经骨骼肌萎缩和纤维生成。
{"title":"Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction.","authors":"Yaoxian Xiang,&nbsp;Zongqi You,&nbsp;Xinying Huang,&nbsp;Junxi Dai,&nbsp;Junpeng Zhang,&nbsp;Shuqi Nie,&nbsp;Lei Xu,&nbsp;Junjian Jiang,&nbsp;Jianguang Xu","doi":"10.1186/s13395-022-00302-y","DOIUrl":"https://doi.org/10.1186/s13395-022-00302-y","url":null,"abstract":"<p><strong>Background: </strong>Progerin elevates atrophic gene expression and helps modify the nuclear membrane to cause severe muscle pathology, which is similar to muscle weakness in the elderly, to alter the development and function of the skeletal muscles. Stress-induced premature senescence (SIPS), a state of cell growth arrest owing to such stimuli as oxidation, can be caused by progerin. However, evidence for whether SIPS-induced progerin accumulation is connected to denervation-induced muscle atrophy is not sufficient.</p><p><strong>Methods: </strong>Flow cytometry and a reactive oxygen species (ROS) as well as inducible nitric oxide synthase (iNOS) inhibitors were used to assess the effect of oxidation on protein (p53), progerin, and nuclear progerin-p53 interaction in the denervated muscles of models of mice suffering from sciatic injury. Loss-of-function approach with the targeted deletion of p53 was used to assess connection among SIPS, denervated muscle atrophy, and fibrogenesis.</p><p><strong>Results: </strong>The augmentation of ROS and iNOS-derived NO in the denervated muscles of models of mice suffering from sciatic injury upregulates p53 and progerin. The abnormal accumulation of progerin in the nuclear membrane as well as the activation of nuclear progerin-p53 interaction triggered premature senescence in the denervated muscle cells of mice. The p53-dependent SIPS in denervated muscles contributes to their atrophy and fibrogenesis.</p><p><strong>Conclusion: </strong>Oxidative stress-triggered premature senescence via nuclear progerin-p53 interaction that promotes denervated skeletal muscular atrophy and fibrogenesis.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40559279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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: 3
Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice. 脊髓性肌萎缩小鼠骨骼肌中扭扭和Fn14的失调。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-07-28 DOI: 10.1186/s13395-022-00301-z
Katharina E Meijboom, Emma R Sutton, Eve McCallion, Emily McFall, Daniel Anthony, Benjamin Edwards, Sabrina Kubinski, Ines Tapken, Ines Bünermann, Gareth Hazell, Nina Ahlskog, Peter Claus, Kay E Davies, Rashmi Kothary, Matthew J A Wood, Melissa Bowerman

Background: Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle.

Methods: We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-; SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations.

Results: Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/-, and Fn14-/- mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models.

Conclusions: Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

背景:脊髓性肌萎缩症(SMA)是一种由存活运动神经元(SMN)蛋白耗损引起的儿童神经肌肉疾病。SMA的特点是脊髓运动神经元选择性死亡,导致进行性肌肉萎缩。SMA骨骼肌的丧失是失神经支配引起的肌肉萎缩和内在肌肉病变的结合。阐明所涉及的途径对于确定促成和维持肌肉病理的关键分子是必不可少的。肿瘤坏死因子样细胞凋亡弱诱导剂(TWEAK)/TNF受体超家族成员成纤维细胞生长因子诱导14 (Fn14)通路已被证明在成人去神经支配诱导的肌肉萎缩以及肌肉增殖、分化和代谢的调节中发挥关键作用。然而,尚不清楚这一途径在高动态和发育中的肌肉中是否重要。方法:因此,我们研究了TWEAK/Fn14通路在SMA肌肉病理中的潜在作用,使用重度台湾Smn-/-;SMN2和较轻的Smn2B/- SMA小鼠,在出生后的前三周经历进行性神经肌肉衰退。我们还使用断奶前野生型(WT)动物去神经支配和肌肉损伤的实验模型以及C2C12肌肉细胞中sirna介导的敲低来进行额外的机制研究。结果:在这里,我们报告了在两种SMA小鼠模型的骨骼肌疾病进展过程中,Tweak、Fn14和先前提出的下游效应物的表达显著失调。此外,C2C12成肌细胞中sirna介导的Smn敲低表明Smn与TWEAK/Fn14通路之间存在遗传相互作用。对SMA、Tweak-/-和Fn14-/-小鼠的进一步分析显示,肌病、肌肉发生和葡萄糖代谢途径失调是骨骼肌的共同特征,为支持Tweak /Fn14途径与Smn之间的关系提供了进一步的证据。最后,应用TWEAK/Fn14激动剂Fc-TWEAK改善了两种SMA小鼠模型的疾病表型。结论:我们的研究提供了对SMA肌肉病理的潜在分子参与者的机制见解,以及对肌肉发育中TWEAK/Fn14通路可能的差异反应的见解。
{"title":"Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice.","authors":"Katharina E Meijboom,&nbsp;Emma R Sutton,&nbsp;Eve McCallion,&nbsp;Emily McFall,&nbsp;Daniel Anthony,&nbsp;Benjamin Edwards,&nbsp;Sabrina Kubinski,&nbsp;Ines Tapken,&nbsp;Ines Bünermann,&nbsp;Gareth Hazell,&nbsp;Nina Ahlskog,&nbsp;Peter Claus,&nbsp;Kay E Davies,&nbsp;Rashmi Kothary,&nbsp;Matthew J A Wood,&nbsp;Melissa Bowerman","doi":"10.1186/s13395-022-00301-z","DOIUrl":"https://doi.org/10.1186/s13395-022-00301-z","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle.</p><p><strong>Methods: </strong>We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn<sup>-/-</sup>; SMN2 and the less severe Smn<sup>2B/-</sup> SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations.</p><p><strong>Results: </strong>Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak<sup>-/-</sup>, and Fn14<sup>-/-</sup> mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models.</p><p><strong>Conclusions: </strong>Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9331072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40571245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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: 3
Differences in muscle satellite cell dynamics during muscle hypertrophy and regeneration. 肌肉肥大和再生过程中肌肉卫星细胞动态的差异。
IF 5.3 2区 医学 Q2 CELL BIOLOGY Pub Date : 2022-07-06 DOI: 10.1186/s13395-022-00300-0
So-Ichiro Fukada, Tatsuyoshi Higashimoto, Akihiro Kaneshige

Skeletal muscle homeostasis and function are ensured by orchestrated cellular interactions among several types of cells. A noticeable aspect of skeletal muscle biology is the drastic cell-cell communication changes that occur in multiple scenarios. The process of recovering from an injury, which is known as regeneration, has been relatively well investigated. However, the cellular interplay that occurs in response to mechanical loading, such as during resistance training, is poorly understood compared to regeneration. During muscle regeneration, muscle satellite cells (MuSCs) rebuild multinuclear myofibers through a stepwise process of proliferation, differentiation, fusion, and maturation, whereas during mechanical loading-dependent muscle hypertrophy, MuSCs do not undergo such stepwise processes (except in rare injuries) because the nuclei of MuSCs become directly incorporated into the mature myonuclei. In this review, six specific examples of such differences in MuSC dynamics between regeneration and hypertrophy processes are discussed.

骨骼肌的平衡和功能是由多种类型细胞之间协调的细胞相互作用来保证的。骨骼肌生物学的一个显著特点是在多种情况下发生的剧烈的细胞间通讯变化。对受伤后的恢复过程(即再生)的研究相对较多。然而,与再生相比,人们对抗阻训练等机械负荷时发生的细胞相互作用了解甚少。在肌肉再生过程中,肌肉卫星细胞(MuSCs)通过增殖、分化、融合和成熟的逐步过程重建多核肌纤维,而在依赖机械负荷的肌肉肥大过程中,MuSCs 无需经历此类逐步过程(罕见损伤除外),因为 MuSCs 的细胞核会直接融入成熟的肌核中。在本综述中,将讨论再生和肥大过程中肌肉干细胞动态差异的六个具体实例。
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引用次数: 0
High-throughput muscle fiber typing from RNA sequencing data. 基于RNA测序数据的高通量肌纤维分型。
IF 4.9 2区 医学 Q1 Medicine Pub Date : 2022-07-02 DOI: 10.1186/s13395-022-00299-4
Nikolay Oskolkov, Malgorzata Santel, Hemang M Parikh, Ola Ekström, Gray J Camp, Eri Miyamoto-Mikami, Kristoffer Ström, Bilal Ahmad Mir, Dmytro Kryvokhyzha, Mikko Lehtovirta, Hiroyuki Kobayashi, Ryo Kakigi, Hisashi Naito, Karl-Fredrik Eriksson, Björn Nystedt, Noriyuki Fuku, Barbara Treutlein, Svante Pääbo, Ola Hansson

Background: Skeletal muscle fiber type distribution has implications for human health, muscle function, and performance. This knowledge has been gathered using labor-intensive and costly methodology that limited these studies. Here, we present a method based on muscle tissue RNA sequencing data (totRNAseq) to estimate the distribution of skeletal muscle fiber types from frozen human samples, allowing for a larger number of individuals to be tested.

Methods: By using single-nuclei RNA sequencing (snRNAseq) data as a reference, cluster expression signatures were produced by averaging gene expression of cluster gene markers and then applying these to totRNAseq data and inferring muscle fiber nuclei type via linear matrix decomposition. This estimate was then compared with fiber type distribution measured by ATPase staining or myosin heavy chain protein isoform distribution of 62 muscle samples in two independent cohorts (n = 39 and 22).

Results: The correlation between the sequencing-based method and the other two were rATPas = 0.44 [0.13-0.67], [95% CI], and rmyosin = 0.83 [0.61-0.93], with p = 5.70 × 10-3 and 2.00 × 10-6, respectively. The deconvolution inference of fiber type composition was accurate even for very low totRNAseq sequencing depths, i.e., down to an average of ~ 10,000 paired-end reads.

Conclusions: This new method ( https://github.com/OlaHanssonLab/PredictFiberType ) consequently allows for measurement of fiber type distribution of a larger number of samples using totRNAseq in a cost and labor-efficient way. It is now feasible to study the association between fiber type distribution and e.g. health outcomes in large well-powered studies.

背景:骨骼肌纤维类型分布与人体健康、肌肉功能和运动表现有关。这些知识是通过劳动密集型和昂贵的方法收集的,这限制了这些研究。在这里,我们提出了一种基于肌肉组织RNA测序数据(totRNAseq)的方法来估计冷冻人体样本中骨骼肌纤维类型的分布,从而允许更多的个体进行测试。方法:以单核RNA测序(snRNAseq)数据为参考,对聚类基因标记的基因表达进行平均,得到聚类表达特征,并将其应用于totRNAseq数据,通过线性矩阵分解推断肌纤维核类型。然后将这一估计与两个独立队列(n = 39和22)中62个肌肉样本的atp酶染色测量的纤维类型分布或肌球蛋白重链蛋白异构体分布进行比较。结果:基于测序的方法与其他两种方法的相关性为rATPas = 0.44 [0.13-0.67], [95% CI], rmyosin = 0.83 [0.61-0.93], p分别为5.70 × 10-3和2.00 × 10-6。即使对于非常低的totRNAseq测序深度,即平均到~ 10,000对末端读取,纤维类型组成的反卷积推断也是准确的。结论:这种新方法(https://github.com/OlaHanssonLab/PredictFiberType)因此可以使用totRNAseq以一种成本和劳动效率高的方式测量大量样品的纤维类型分布。现在,研究纤维类型分布与健康结果之间的关系是可行的。
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引用次数: 5
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Skeletal Muscle
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