Skeletal Muscle最新文献

{"title":"Amiloride ameliorates muscle wasting in cancer cachexia through inhibiting tumor-derived exosome release.","authors":"Lin Zhou,&nbsp;Tong Zhang,&nbsp;Wei Shao,&nbsp;Ruohan Lu,&nbsp;Lin Wang,&nbsp;Haisheng Liu,&nbsp;Bin Jiang,&nbsp;Shiqin Li,&nbsp;Huiqin Zhuo,&nbsp;Suheng Wang,&nbsp;Qinxi Li,&nbsp;Caihua Huang,&nbsp;Donghai Lin","doi":"10.1186/s13395-021-00274-5","DOIUrl":"https://doi.org/10.1186/s13395-021-00274-5","url":null,"abstract":"<p><strong>Background: </strong>Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of the amiloride treatment for ameliorating muscle wasting in murine models of cancer cachexia.</p><p><strong>Methods: </strong>The CT26 and LLC tumor cells were subcutaneously injected into mice to induce colon cancer cachexia and lung cancer cachexia, respectively. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 model and the LLC model were separately characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius.</p><p><strong>Results: </strong>The CT26 and LLC cachexia models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue, and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. Both the CT26 and LLC cachexia mice showed increased plasma exosome densities which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis, and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius.</p><p><strong>Conclusions: </strong>Amiloride ameliorates cachectic muscle wasting and alleviates cancer cachexia progression through inhibiting tumor-derived exosome release. Our results are beneficial to understanding the underlying molecular mechanisms, shedding light on the potentials of amiloride in cachexia therapy.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00274-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39158619","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}

{"title":"Origins, potency, and heterogeneity of skeletal muscle fibro-adipogenic progenitors-time for new definitions.","authors":"Osvaldo Contreras,&nbsp;Fabio M V Rossi,&nbsp;Marine Theret","doi":"10.1186/s13395-021-00265-6","DOIUrl":"10.1186/s13395-021-00265-6","url":null,"abstract":"<p><p>Striated muscle is a highly plastic and regenerative organ that regulates body movement, temperature, and metabolism-all the functions needed for an individual's health and well-being. The muscle connective tissue's main components are the extracellular matrix and its resident stromal cells, which continuously reshape it in embryonic development, homeostasis, and regeneration. Fibro-adipogenic progenitors are enigmatic and transformative muscle-resident interstitial cells with mesenchymal stem/stromal cell properties. They act as cellular sentinels and physiological hubs for adult muscle homeostasis and regeneration by shaping the microenvironment by secreting a complex cocktail of extracellular matrix components, diffusible cytokines, ligands, and immune-modulatory factors. Fibro-adipogenic progenitors are the lineage precursors of specialized cells, including activated fibroblasts, adipocytes, and osteogenic cells after injury. Here, we discuss current research gaps, potential druggable developments, and outstanding questions about fibro-adipogenic progenitor origins, potency, and heterogeneity. Finally, we took advantage of recent advances in single-cell technologies combined with lineage tracing to unify the diversity of stromal fibro-adipogenic progenitors. Thus, this compelling review provides new cellular and molecular insights in comprehending the origins, definitions, markers, fate, and plasticity of murine and human fibro-adipogenic progenitors in muscle development, homeostasis, regeneration, and repair.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00265-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39140629","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}

{"title":"Niclosamide ethanolamine ameliorates diabetes-related muscle wasting by inhibiting autophagy.","authors":"Yuchun Cai,&nbsp;Hongyue Zhan,&nbsp;Wenci Weng,&nbsp;Yao Wang,&nbsp;Pengxun Han,&nbsp;Xuewen Yu,&nbsp;Mumin Shao,&nbsp;Huili Sun","doi":"10.1186/s13395-021-00272-7","DOIUrl":"https://doi.org/10.1186/s13395-021-00272-7","url":null,"abstract":"<p><strong>Background: </strong>Diabetes-related muscle wasting is one of the devastating complications of diabetes, which is associated with muscle autophagy due to insulin-mediated glucose starvation. However, treatment for diabetes-related muscle wasting is limited. Our previous study already found that niclosamide ethanolamine salt has the therapeutic effects on insulin deficiency of type 1 diabetes mice and muscle wasting induced by doxorubicin. Therefore, we aim to investigate the therapeutic effects of niclosamide ethanolamine salt on diabetes-induced muscle wasting and to explore whether the mechanism is associated with muscle autophagy.</p><p><strong>Methods: </strong>Type 1 diabetes mice were induced by intraperitoneal injection of streptozotocin, then were fed with regular diet supplemented with 10 g/kg niclosamide ethanolamine salt. The whole experiment lasted for 8 weeks. At the end of the study, grip strength, weights of tibialis anterior, gastrocnemius, soleus, and extensor digitorum longus muscle were measured. Tibialis anterior muscles stained with PAS were used for evaluating the fiber cross sectional area. Immunofluorescence analysis of myosin heavy chain expression in extensor digitorum longus and soleus muscle was used for determining the composition of the muscle fiber type. Electronic microscopy was applied to observe the autophagy in the atrophied muscle. Serum insulin levels and fasting blood glucose were also measured. Tissues of gastrocnemius muscle were used for detecting the expression of the proteins related to autophagy.</p><p><strong>Results: </strong>In this study, we found that niclosamide ethanolamine salt could ameliorate muscle atrophy in the type 1 diabetes mice as well, such as enhancing the declined grip strength, improving limb weight and increasing the numbers of glycolytic muscle fiber. Electron microscopy also confirmed that there did exist abundant autophagic vacuoles in the atrophied muscle of the type 1 diabetes mice. Specifically, niclosamide ethanolamine salt could reduce the over expression of autophagy-related proteins, including p-AMPK (Thr172), FoxO3a, p-ULK1 (Ser555), LC3B II, and p-p38 in gastrocnemius muscle of the type 1 diabetes mice.</p><p><strong>Conclusion: </strong>Niclosamide ethanolamine salt could ameliorate muscle wasting. The mechanisms underlying might be associated with inhibition of muscle autophagy.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00272-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39079223","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}

{"title":"Transcription factor signal transducer and activator of transcription 6 (STAT6) is an inhibitory factor for adult myogenesis.","authors":"Mitsutoshi Kurosaka,&nbsp;Yuji Ogura,&nbsp;Shuichi Sato,&nbsp;Kazuhisa Kohda,&nbsp;Toshiya Funabashi","doi":"10.1186/s13395-021-00271-8","DOIUrl":"https://doi.org/10.1186/s13395-021-00271-8","url":null,"abstract":"<p><strong>Background: </strong>The signal transducer and activator of transcription 6 (STAT6) transcription factor plays a vitally important role in immune cells, where it is activated mainly by interleukin-4 (IL-4). Because IL-4 is an essential cytokine for myotube formation, STAT6 might also be involved in myogenesis as part of IL-4 signaling. This study was conducted to elucidate the role of STAT6 in adult myogenesis in vitro and in vivo.</p><p><strong>Methods: </strong>Myoblasts were isolated from male mice and were differentiated on a culture dish to evaluate the change in STAT6 during myotube formation. Then, the effects of STAT6 overexpression and inhibition on proliferation, differentiation, and fusion in those cells were studied. Additionally, to elucidate the myogenic role of STAT6 in vivo, muscle regeneration after injury was evaluated in STAT6 knockout mice.</p><p><strong>Results: </strong>IL-4 can increase STAT6 phosphorylation, but STAT6 phosphorylation decreased during myotube formation in culture. STAT6 overexpression decreased, but STAT6 knockdown increased the differentiation index and the fusion index. Results indicate that STAT6 inhibited myogenin protein expression. Results of in vivo experiments show that STAT6 knockout mice exhibited better regeneration than wild-type mice 5 days after cardiotoxin-induced injury. It is particularly interesting that results obtained using cells from STAT6 knockout mice suggest that this STAT6 inhibitory action for myogenesis was not mediated by IL-4 but might instead be associated with p38 mitogen-activated protein kinase phosphorylation. However, STAT6 was not involved in the proliferation of myogenic cells in vitro and in vivo.</p><p><strong>Conclusion: </strong>Results suggest that STAT6 functions as an inhibitor of adult myogenesis. Moreover, results suggest that the IL-4-STAT6 signaling axis is unlikely to be responsible for myotube formation.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00271-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39031313","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}

{"title":"Single cell RNA-seq analysis of the flexor digitorum brevis mouse myofibers.","authors":"Rohan X Verma,&nbsp;Suraj Kannan,&nbsp;Brian L Lin,&nbsp;Katherine M Fomchenko,&nbsp;Tim O Nieuwenhuis,&nbsp;Arun H Patil,&nbsp;Clarisse Lukban,&nbsp;Xiaoping Yang,&nbsp;Karen Fox-Talbot,&nbsp;Matthew N McCall,&nbsp;Chulan Kwon,&nbsp;David A Kass,&nbsp;Avi Z Rosenberg,&nbsp;Marc K Halushka","doi":"10.1186/s13395-021-00269-2","DOIUrl":"https://doi.org/10.1186/s13395-021-00269-2","url":null,"abstract":"<p><strong>Background: </strong>Skeletal muscle myofibers can be separated into functionally distinct cell types that differ in gene and protein expression. Current single cell expression data is generally based upon single nucleus RNA, rather than whole myofiber material. We examined if a whole-cell flow sorting approach could be applied to perform single cell RNA-seq (scRNA-seq) in a single muscle type.</p><p><strong>Methods: </strong>We performed deep, whole cell, scRNA-seq on intact and fragmented skeletal myofibers from the mouse fast-twitch flexor digitorum brevis muscle utilizing a flow-gated method of large cell isolation. We performed deep sequencing of 763 intact and fragmented myofibers.</p><p><strong>Results: </strong>Quality control metrics across the different gates indicated only 171 of these cells were optimal, with a median read count of 239,252 and an average of 12,098 transcripts per cell. scRNA-seq identified three clusters of myofibers (a slow/fast 2A cluster and two fast 2X clusters). Comparison to a public skeletal nuclear RNA-seq dataset demonstrated a diversity in transcript abundance by method. RISH validated multiple genes across fast and slow twitch skeletal muscle types.</p><p><strong>Conclusion: </strong>This study introduces and validates a method to isolate intact skeletal muscle myofibers to generate deep expression patterns and expands the known repertoire of fiber-type-specific genes.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00269-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38922154","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}

{"title":"Nanopattern surface improves cultured human myotube maturation.","authors":"Jessica Brunetti,&nbsp;Stéphane Koenig,&nbsp;Arthur Monnier,&nbsp;Maud Frieden","doi":"10.1186/s13395-021-00268-3","DOIUrl":"https://doi.org/10.1186/s13395-021-00268-3","url":null,"abstract":"<p><strong>Background: </strong>In vitro maturation of human primary myoblasts using 2D culture remains a challenging process and leads to immature fibers with poor internal organization and function. This would however represent a valuable system to study muscle physiology or pathophysiology from patient myoblasts, at a single-cell level.</p><p><strong>Methods: </strong>Human primary myoblasts were cultured on 800-nm wide striated surface between two layers of Matrigel, and in a media supplemented with an inhibitor of TGFβ receptor. Gene expression, immunofluorescence, and Ca²⁺ measurements upon electrical stimulations were performed at various time points during maturation to assess the organization and function of the myotubes.</p><p><strong>Results: </strong>We show that after 10 days in culture, myotubes display numerous functional acetylcholine receptor clusters and express the adult isoforms of myosin heavy chain and dihydropyridine receptor. In addition, the myotubes are internally well organized with striations of α-actinin and STIM1, and occasionally ryanodine receptor 1. We also demonstrate that the myotubes present robust Ca²⁺ responses to repetitive electrical stimulations.</p><p><strong>Conclusion: </strong>The present method describes a fast and efficient system to obtain well matured and functional myotubes in 2D culture allowing thorough analysis of single-cell Ca²⁺ signals.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00268-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38962504","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}

{"title":"Multi-omics reveals age-related differences in the diaphragm response to mechanical ventilation: a pilot study.","authors":"Qiong Lyu, Ya Wen, Xiang Zhang, Alex B Addinsall, Nicola Cacciani, Lars Larsson","doi":"10.1186/s13395-021-00267-4","DOIUrl":"10.1186/s13395-021-00267-4","url":null,"abstract":"<p><strong>Background: </strong>Old age is associated with a significantly increased mortality in COVID-19 patients exposed to long-term controlled mechanical ventilation (CMV) and suggested to be due to the hyperinflammatory response associated with the viral infection. However, our understanding of age-related differences in the response to CMV in the absence of a viral infection remains insufficient.</p><p><strong>Methods: </strong>Young (7-8 months) and old (28-32 months) F344 BN hybrid rats were exposed to the ICU condition for 5 days, i.e., complete immobilization, mechanical ventilation, and extensive monitoring. Transcriptomic (RNA-Seq) and proteomics (Proximity Extension Assay) analyses of the diaphragm and proteomics analysis of plasma were conducted to investigate the molecular differences between young and old rats exposed to the ICU condition.</p><p><strong>Results: </strong>According to multi-omics analyses, significant differences were observed in the diaphragm between young and old rats in response to 5 days CMV and immobilization. In young rats, metabolic pathways were primarily downregulated in response to immobilization (post-synaptic blockade of neuromuscular transmission). In old rats, on the other hand, dramatic immune and inflammatory responses were observed, i.e., an upregulation of specific related pathways such as \"IL-17 signaling pathway\", along with a higher level of inflammatory factors and cytokine/chemokine in plasma.</p><p><strong>Conclusions: </strong>The dramatically increased mortality in old ICU patients with COVID-19-associated hyperinflammation and cytokine storm need not only reflect the viral infection but may also be associated with the ventilator induced diaphragm dysfunction (VIDD) and hyperinflammatory responses induced by long-term CMV per se. Although mechanical ventilation is a life-saving intervention in COVID-19 ICU patients, CMV should be cautiously used especially in old age and other means of respiratory support may be considered, such as negative pressure ventilation.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38954468","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}

{"title":"Severe acute myopathy following SARS-CoV-2 infection: a case report and review of recent literature.","authors":"Badrul Islam,&nbsp;Mohiuddin Ahmed,&nbsp;Zhahirul Islam,&nbsp;S M Begum","doi":"10.1186/s13395-021-00266-5","DOIUrl":"https://doi.org/10.1186/s13395-021-00266-5","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV2 virus could be potentially myopathic. Serum creatinine phosphokinase (CPK) is frequently found elevated in severe SARS-CoV2 infection, which indicates skeletal muscle damage precipitating limb weakness or even ventilatory failure.</p><p><strong>Case presentation: </strong>We addressed such a patient in his forties presented with features of severe SARS-CoV2 pneumonia and high serum CPK. He developed severe sepsis and acute respiratory distress syndrome (ARDS) and received intravenous high dose corticosteroid and tocilizumab to counter SARS-CoV2 associated cytokine surge. After 10 days of mechanical ventilation (MV), weaning was unsuccessful albeit apparently clear lung fields, having additionally severe and symmetric limb muscle weakness. Ancillary investigations in addition with serum CPK, including electromyogram, muscle biopsy, and muscle magnetic resonance imaging (MRI) suggested acute myopathy possibly due to skeletal myositis.</p><p><strong>Conclusion: </strong>We wish to stress that myopathogenic medication in SARS-CoV2 pneumonia should be used with caution. Additionally, serum CPK could be a potential marker to predict respiratory failure in SARS-CoV2 pneumonia as skeletal myopathy affecting chest muscles may contribute ventilatory failure on top of oxygenation failure due to SARS-CoV2 pneumonia.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00266-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38896041","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}

{"title":"Retraction Note to: Exercise-induced mitochondrial p53 repairs mtDNA mutations in mutator mice.","authors":"Adeel Safdar,&nbsp;Konstantin Khrapko,&nbsp;James M Flynn,&nbsp;Ayesha Saleem,&nbsp;Michael De Lisio,&nbsp;Adam P W Johnston,&nbsp;Yevgenya Kratysberg,&nbsp;Imtiaz A Samjoo,&nbsp;Yu Kitaoka,&nbsp;Daniel I Ogborn,&nbsp;Jonathan P Little,&nbsp;Sandeep Raha,&nbsp;Gianni Parise,&nbsp;Mahmood Akhtar,&nbsp;Bart P Hettinga,&nbsp;Glenn C Rowe,&nbsp;Zoltan Arany,&nbsp;Tomas A Prolla,&nbsp;Mark A Tarnopolsky","doi":"10.1186/s13395-021-00264-7","DOIUrl":"https://doi.org/10.1186/s13395-021-00264-7","url":null,"abstract":"","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00264-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25542480","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}

{"title":"Muscle atrophy induced by overexpression of ALAS2 is related to muscle mitochondrial dysfunction.","authors":"Yahui Peng,&nbsp;Jihong Li,&nbsp;Dixian Luo,&nbsp;Shuai Zhang,&nbsp;Sijia Li,&nbsp;Dayong Wang,&nbsp;Xidi Wang,&nbsp;Zhujun Zhang,&nbsp;Xue Wang,&nbsp;Changhui Sun,&nbsp;Xu Gao,&nbsp;Yang Hui,&nbsp;Rongzhang He","doi":"10.1186/s13395-021-00263-8","DOIUrl":"https://doi.org/10.1186/s13395-021-00263-8","url":null,"abstract":"<p><strong>Background: </strong>ALAS2 (delta-aminolevulinate synthase 2) is one of the two isoenzymes catalyzing the synthesis of delta-aminolevulinic acid (ALA), which is the first precursor of heme synthesis. ALAS2-overexpressing transgenic mice (Tg mice) showed syndrome of porphyria, a series of diseases related to the heme anabolism deficiency. Tg mice showed an obvious decrease in muscle size. Muscle atrophy results from a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to a decrease in myofiber size due to loss of contractile proteins, organelles, nuclei, and cytoplasm.</p><p><strong>Methods: </strong>The forelimb muscle grip strength of age-matched ALAS-2 transgenic mice (Tg mice) and wild-type mice (WT mice) were measured with an automated grip strength meter. The activities of serum LDH and CK-MB were measured by Modular DPP. The histology of skeletal muscle (quadriceps femoris and gastrocnemius) was observed by hematoxylin and eosin (HE) staining, immunohistochemistry, and transmission electron microscope. Real-time PCR was used to detect mtDNA content and UCP3 mRNA expression. Evans blue dye staining was used to detect the membrane damage of the muscle fiber. Single skeletal muscle fiber diameter was measured by single-fiber analyses. Muscle adenosine triphosphate (ATP) levels were detected by a luminometric assay with an ATP assay kit.</p><p><strong>Results: </strong>Compared with WT mice, the strength of forelimb muscle and mass of gastrocnemius were decreased in Tg mice. The activities of serum CK-MB and LDH, the number of central nuclei fibers, and Evans blue positive fibers were more than those in WT mice, while the diameter of single fibers was smaller, which were associated with suppressed expression levels of MHC, myoD1, dystrophin, atrogin1, and MuRF1. Re-expression of eMyHC was only showed in the quadriceps of Tg mice, but not in WT mice. Muscle mitochondria in Tg mice showed dysfunction with descented ATP production and mtDNA content, downregulated UCP3 mRNA expression, and swelling of mitochondria.</p><p><strong>Conclusion: </strong>ALAS2 overexpressing-transgenic mice (Tg mice) showed muscle dystrophy, which was associated with decreased atrogin-1 and MuRF-1, and closely related to mitochondrial dysfunction.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/s13395-021-00263-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25531634","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}