Pub Date : 2022-11-29DOI: 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.
{"title":"Limb-girdle muscular dystrophy type 2B causes HDL-C abnormalities in patients and statin-resistant muscle wasting in dysferlin-deficient mice.","authors":"Zoe White, Zeren Sun, Elodie Sauge, Dan Cox, Graham Donen, Dmitri Pechkovsky, Volker Straub, Gordon A Francis, Pascal Bernatchez","doi":"10.1186/s13395-022-00308-6","DOIUrl":"https://doi.org/10.1186/s13395-022-00308-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9706908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10526261","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}
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.
{"title":"Macroglossia and less advanced dystrophic change in the tongue muscle of the Duchenne muscular dystrophy rat.","authors":"Keitaro Yamanouchi, Yukie Tanaka, Masanari Ikeda, Shizuka Kato, Ryosuke Okino, Hiroki Nishi, Fumihiko Hakuno, Shin-Ichiro Takahashi, James Chambers, Takashi Matsuwaki, Kazuyuki Uchida","doi":"10.1186/s13395-022-00307-7","DOIUrl":"https://doi.org/10.1186/s13395-022-00307-7","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Muscular dystrophy is less advanced in the tongue muscle compared to the masseter muscle in the DMD rat.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9580129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40339240","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}
Pub Date : 2022-09-29DOI: 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。
{"title":"Megaconial congenital muscular dystrophy due to novel CHKB variants: a case report and literature review.","authors":"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","doi":"10.1186/s13395-022-00306-8","DOIUrl":"https://doi.org/10.1186/s13395-022-00306-8","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Case presentation: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9524117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40383594","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}
Pub Date : 2022-09-12DOI: 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.
{"title":"Mouse models of SMA show divergent patterns of neuronal vulnerability and resilience.","authors":"Victoria Woschitz, Irene Mei, Eva Hedlund, 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}
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.
{"title":"Identification of the co-differentially expressed hub genes involved in the endogenous protective mechanism against ventilator-induced diaphragm dysfunction.","authors":"Dong Zhang, Wenyan Hao, Qi Niu, Dongdong Xu, 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}
Pub Date : 2022-08-15DOI: 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.
{"title":"Prolonged FOS activity disrupts a global myogenic transcriptional program by altering 3D chromatin architecture in primary muscle progenitor cells.","authors":"A Rasim Barutcu, Gabriel Elizalde, Alfredo E Gonzalez, Kartik Soni, John L Rinn, Amy J Wagers, Albert E Almada","doi":"10.1186/s13395-022-00303-x","DOIUrl":"10.1186/s13395-022-00303-x","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9838031","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}
Pub Date : 2022-07-29DOI: 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.
{"title":"Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction.","authors":"Yaoxian Xiang, Zongqi You, Xinying Huang, Junxi Dai, Junpeng Zhang, Shuqi Nie, Lei Xu, Junjian Jiang, 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}
Pub Date : 2022-07-28DOI: 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.
{"title":"Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice.","authors":"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","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}
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.
{"title":"Differences in muscle satellite cell dynamics during muscle hypertrophy and regeneration.","authors":"So-Ichiro Fukada, Tatsuyoshi Higashimoto, Akihiro Kaneshige","doi":"10.1186/s13395-022-00300-0","DOIUrl":"10.1186/s13395-022-00300-0","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2022-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40576328","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}
Pub Date : 2022-07-02DOI: 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.
{"title":"High-throughput muscle fiber typing from RNA sequencing data.","authors":"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","doi":"10.1186/s13395-022-00299-4","DOIUrl":"https://doi.org/10.1186/s13395-022-00299-4","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>The correlation between the sequencing-based method and the other two were r<sub>ATPas</sub> = 0.44 [0.13-0.67], [95% CI], and r<sub>myosin</sub> = 0.83 [0.61-0.93], with p = 5.70 × 10<sup>-3</sup> and 2.00 × 10<sup>-6</sup>, 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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2022-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250227/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40577681","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}