Background: The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy.
Methods: Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated.
Results: The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice.
Conclusions: Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults.
{"title":"IL-33-ST2 signaling in fibro-adipogenic progenitors alleviates immobilization-induced muscle atrophy in mice.","authors":"Yoshiyuki Takahashi, Masaki Yoda, Osahiko Tsuji, Keisuke Horiuchi, Kota Watanabe, Masaya Nakamura","doi":"10.1186/s13395-024-00338-2","DOIUrl":"10.1186/s13395-024-00338-2","url":null,"abstract":"<p><strong>Background: </strong>The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy.</p><p><strong>Methods: </strong>Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated.</p><p><strong>Results: </strong>The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice.</p><p><strong>Conclusions: </strong>Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"14 1","pages":"6"},"PeriodicalIF":4.9,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10983726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336820","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 : 2024-03-07DOI: 10.1186/s13395-024-00336-4
Suradip Das, Melanie C. Hilman, Feikun Yang, Foteini Mourkioti, Wenli Yang, D. Kacy Cullen
Neurovascular cells have wide-ranging implications on skeletal muscle biology regulating myogenesis, maturation, and regeneration. Although several in vitro studies have investigated how motor neurons and endothelial cells interact with skeletal myocytes independently, there is limited knowledge about the combined effect of neural and vascular cells on muscle maturation and development. Here, we report a triculture system comprising human-induced pluripotent stem cell (iPSC)-derived skeletal myocytes, human iPSC-derived motor neurons, and primary human endothelial cells maintained under controlled media conditions. Briefly, iPSCs were differentiated to generate skeletal muscle progenitor cells (SMPCs). These SMPCs were seeded at a density of 5 × 104 cells/well in 12-well plates and allowed to differentiate for 7 days before adding iPSC-derived motor neurons at a concentration of 0.5 × 104 cells/well. The neuromuscular coculture was maintained for another 7 days in coculture media before addition of primary human umbilical vein endothelial cells (HUVEC) also at 0.5 × 104 cells/well. The triculture was maintained for another 7 days in triculture media comprising equal portions of muscle differentiation media, coculture media, and vascular media. Extensive morphological, genetic, and molecular characterization was performed to understand the combined and individual effects of neural and vascular cells on skeletal muscle maturation. We observed that motor neurons independently promoted myofiber fusion, upregulated neuromuscular junction genes, and maintained a molecular niche supportive of muscle maturation. Endothelial cells independently did not support myofiber fusion and downregulated expression of LRP4 but did promote expression of type II specific myosin isoforms. However, neurovascular cells in combination exhibited additive increases in myofiber fusion and length, enhanced production of Agrin, along with upregulation of several key genes like MUSK, RAPSYN, DOK-7, and SLC2A4. Interestingly, more divergent effects were observed in expression of genes like MYH8, MYH1, MYH2, MYH4, and LRP4 and secretion of key molecular factors like amphiregulin and IGFBP-4. Neurovascular cells when cultured in combination with skeletal myocytes promoted myocyte fusion with concomitant increase in expression of various neuromuscular genes. This triculture system may be used to gain a deeper understanding of the effects of the neurovascular niche on skeletal muscle biology and pathophysiology.
{"title":"Motor neurons and endothelial cells additively promote development and fusion of human iPSC-derived skeletal myocytes","authors":"Suradip Das, Melanie C. Hilman, Feikun Yang, Foteini Mourkioti, Wenli Yang, D. Kacy Cullen","doi":"10.1186/s13395-024-00336-4","DOIUrl":"https://doi.org/10.1186/s13395-024-00336-4","url":null,"abstract":"Neurovascular cells have wide-ranging implications on skeletal muscle biology regulating myogenesis, maturation, and regeneration. Although several in vitro studies have investigated how motor neurons and endothelial cells interact with skeletal myocytes independently, there is limited knowledge about the combined effect of neural and vascular cells on muscle maturation and development. Here, we report a triculture system comprising human-induced pluripotent stem cell (iPSC)-derived skeletal myocytes, human iPSC-derived motor neurons, and primary human endothelial cells maintained under controlled media conditions. Briefly, iPSCs were differentiated to generate skeletal muscle progenitor cells (SMPCs). These SMPCs were seeded at a density of 5 × 104 cells/well in 12-well plates and allowed to differentiate for 7 days before adding iPSC-derived motor neurons at a concentration of 0.5 × 104 cells/well. The neuromuscular coculture was maintained for another 7 days in coculture media before addition of primary human umbilical vein endothelial cells (HUVEC) also at 0.5 × 104 cells/well. The triculture was maintained for another 7 days in triculture media comprising equal portions of muscle differentiation media, coculture media, and vascular media. Extensive morphological, genetic, and molecular characterization was performed to understand the combined and individual effects of neural and vascular cells on skeletal muscle maturation. We observed that motor neurons independently promoted myofiber fusion, upregulated neuromuscular junction genes, and maintained a molecular niche supportive of muscle maturation. Endothelial cells independently did not support myofiber fusion and downregulated expression of LRP4 but did promote expression of type II specific myosin isoforms. However, neurovascular cells in combination exhibited additive increases in myofiber fusion and length, enhanced production of Agrin, along with upregulation of several key genes like MUSK, RAPSYN, DOK-7, and SLC2A4. Interestingly, more divergent effects were observed in expression of genes like MYH8, MYH1, MYH2, MYH4, and LRP4 and secretion of key molecular factors like amphiregulin and IGFBP-4. Neurovascular cells when cultured in combination with skeletal myocytes promoted myocyte fusion with concomitant increase in expression of various neuromuscular genes. This triculture system may be used to gain a deeper understanding of the effects of the neurovascular niche on skeletal muscle biology and pathophysiology.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"32 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140056820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Untargeted metabolomics can be used to expand our understanding of the pathogenesis of sarcopenia. However, the metabolic signatures of sarcopenia patients have not been thoroughly investigated. Herein, we explored metabolites associated with sarcopenia by untargeted gas chromatography (GC)/liquid chromatography (LC)–mass spectrometry (MS) and identified possible diagnostic markers. Forty-eight elderly subjects with sarcopenia were age and sex matched with 48 elderly subjects without sarcopenia. We first used untargeted GC/LC–MS to analyze the plasma of these participants and then combined it with a large number of multivariate statistical analyses to analyze the data. Finally, based on a multidimensional analysis of the metabolites, the most critical metabolites were considered to be biomarkers of sarcopenia. According to variable importance in the project (VIP > 1) and the p-value of t-test (p < 0.05), a total of 55 metabolites by GC–MS and 85 metabolites by LC–MS were identified between sarcopenia subjects and normal controls, and these were mostly lipids and lipid-like molecules. Among the top 20 metabolites, seven phosphatidylcholines, seven lysophosphatidylcholines (LysoPCs), phosphatidylinositol, sphingomyelin, palmitamide, L-2-amino-3-oxobutanoic acid, and palmitic acid were downregulated in the sarcopenia group; only ethylamine was upregulated. Among that, three metabolites of LysoPC(17:0), L-2-amino-3-oxobutanoic acid, and palmitic acid showed very good prediction capacity with AUCs of 0.887 (95% CI = 0.817–0.957), 0.836 (95% CI = 0.751–0.921), and 0.805 (95% CI = 0.717–0.893), respectively. These findings show that metabonomic analysis has great potential to be applied to sarcopenia. The identified metabolites could be potential biomarkers and could be used to study sarcopenia pathomechanisms.
非靶向代谢组学可用于扩大我们对肌肉疏松症发病机制的了解。然而，我们尚未对肌肉疏松症患者的代谢特征进行深入研究。在此，我们通过非靶向气相色谱（GC）/液相色谱（LC）-质谱法（MS）研究了与肌肉疏松症相关的代谢物，并确定了可能的诊断标志物。48 名患有肌肉疏松症的老年受试者与 48 名未患有肌肉疏松症的老年受试者在年龄和性别上进行了配对。我们首先使用非靶向气相色谱/液相色谱-质谱法对这些受试者的血浆进行分析，然后结合大量的多元统计分析对数据进行分析。最后，根据对代谢物的多维分析，认为最关键的代谢物是肌肉疏松症的生物标志物。根据变量在项目中的重要性（VIP > 1）和 t 检验的 p 值（p < 0.05），通过气相色谱-质谱联用仪（GC-MS）和液相色谱-质谱联用仪（LC-MS），共鉴定出 55 种代谢物存在于肌肉疏松症受试者和正常对照组之间，其中大部分是脂类和类脂分子。在前20种代谢物中，有7种磷脂酰胆碱、7种溶血磷脂酰胆碱（溶血磷脂酰胆碱）、磷脂酰肌醇、鞘磷脂、棕榈酰胺、L-2-氨基-3-氧代丁酸和棕榈酸在肌肉疏松症组中下调，只有乙胺上调。其中，LysoPC(17:0)、L-2-氨基-3-氧代丁酸和棕榈酸这三种代谢物显示出很好的预测能力，其AUC分别为0.887（95% CI = 0.817-0.957）、0.836（95% CI = 0.751-0.921）和0.805（95% CI = 0.717-0.893）。这些发现表明，代谢组学分析在应用于肌肉疏松症方面具有很大的潜力。所鉴定的代谢物可能是潜在的生物标记物，可用于研究肌肉疏松症的病理机制。
{"title":"Metabolic signatures and potential biomarkers of sarcopenia in suburb-dwelling older Chinese: based on untargeted GC–MS and LC–MS","authors":"Peipei Han, Chunhua Yuan, Xiaoyu Chen, Yuanqing Hu, Xiaodan Hu, Zhangtao Xu, Qi Guo","doi":"10.1186/s13395-024-00337-3","DOIUrl":"https://doi.org/10.1186/s13395-024-00337-3","url":null,"abstract":"Untargeted metabolomics can be used to expand our understanding of the pathogenesis of sarcopenia. However, the metabolic signatures of sarcopenia patients have not been thoroughly investigated. Herein, we explored metabolites associated with sarcopenia by untargeted gas chromatography (GC)/liquid chromatography (LC)–mass spectrometry (MS) and identified possible diagnostic markers. Forty-eight elderly subjects with sarcopenia were age and sex matched with 48 elderly subjects without sarcopenia. We first used untargeted GC/LC–MS to analyze the plasma of these participants and then combined it with a large number of multivariate statistical analyses to analyze the data. Finally, based on a multidimensional analysis of the metabolites, the most critical metabolites were considered to be biomarkers of sarcopenia. According to variable importance in the project (VIP > 1) and the p-value of t-test (p < 0.05), a total of 55 metabolites by GC–MS and 85 metabolites by LC–MS were identified between sarcopenia subjects and normal controls, and these were mostly lipids and lipid-like molecules. Among the top 20 metabolites, seven phosphatidylcholines, seven lysophosphatidylcholines (LysoPCs), phosphatidylinositol, sphingomyelin, palmitamide, L-2-amino-3-oxobutanoic acid, and palmitic acid were downregulated in the sarcopenia group; only ethylamine was upregulated. Among that, three metabolites of LysoPC(17:0), L-2-amino-3-oxobutanoic acid, and palmitic acid showed very good prediction capacity with AUCs of 0.887 (95% CI = 0.817–0.957), 0.836 (95% CI = 0.751–0.921), and 0.805 (95% CI = 0.717–0.893), respectively. These findings show that metabonomic analysis has great potential to be applied to sarcopenia. The identified metabolites could be potential biomarkers and could be used to study sarcopenia pathomechanisms.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"4 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140056713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22DOI: 10.1186/s13395-024-00335-5
Stijn L. M. in ‘t Groen, Marnix Franken, Theresa Bock, Marcus Krüger, Jessica C. de Greef, W. W. M. Pim Pijnappel
Human iPSC-derived 3D-tissue-engineered-skeletal muscles (3D-TESMs) offer advanced technology for disease modelling. However, due to the inherent genetic heterogeneity among human individuals, it is often difficult to distinguish disease-related readouts from random variability. The generation of genetically matched isogenic controls using gene editing can reduce variability, but the generation of isogenic hiPSC-derived 3D-TESMs can take up to 6 months, thereby reducing throughput. Here, by combining 3D-TESM and shRNA technologies, we developed a disease modelling strategy to induce distinct genetic deficiencies in a single hiPSC-derived myogenic progenitor cell line within 1 week. As proof of principle, we recapitulated disease-associated pathology of Duchenne muscular dystrophy and limb-girdle muscular dystrophy type 2A caused by loss of function of DMD and CAPN3, respectively. shRNA-mediated knock down of DMD or CAPN3 induced a loss of contractile function, disruption of tissue architecture, and disease-specific proteomes. Pathology in DMD-deficient 3D-TESMs was partially rescued by a candidate gene therapy treatment using micro-dystrophin, with similar efficacy compared to animal models. These results show that isogenic shRNA-based humanized 3D-TESM models provide a fast, cheap, and efficient tool to model muscular dystrophies and are useful for the preclinical evaluation of novel therapies.
{"title":"A knock down strategy for rapid, generic, and versatile modelling of muscular dystrophies in 3D-tissue-engineered-skeletal muscle","authors":"Stijn L. M. in ‘t Groen, Marnix Franken, Theresa Bock, Marcus Krüger, Jessica C. de Greef, W. W. M. Pim Pijnappel","doi":"10.1186/s13395-024-00335-5","DOIUrl":"https://doi.org/10.1186/s13395-024-00335-5","url":null,"abstract":"Human iPSC-derived 3D-tissue-engineered-skeletal muscles (3D-TESMs) offer advanced technology for disease modelling. However, due to the inherent genetic heterogeneity among human individuals, it is often difficult to distinguish disease-related readouts from random variability. The generation of genetically matched isogenic controls using gene editing can reduce variability, but the generation of isogenic hiPSC-derived 3D-TESMs can take up to 6 months, thereby reducing throughput. Here, by combining 3D-TESM and shRNA technologies, we developed a disease modelling strategy to induce distinct genetic deficiencies in a single hiPSC-derived myogenic progenitor cell line within 1 week. As proof of principle, we recapitulated disease-associated pathology of Duchenne muscular dystrophy and limb-girdle muscular dystrophy type 2A caused by loss of function of DMD and CAPN3, respectively. shRNA-mediated knock down of DMD or CAPN3 induced a loss of contractile function, disruption of tissue architecture, and disease-specific proteomes. Pathology in DMD-deficient 3D-TESMs was partially rescued by a candidate gene therapy treatment using micro-dystrophin, with similar efficacy compared to animal models. These results show that isogenic shRNA-based humanized 3D-TESM models provide a fast, cheap, and efficient tool to model muscular dystrophies and are useful for the preclinical evaluation of novel therapies.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"3 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139927746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-16DOI: 10.1186/s13395-023-00334-y
Jessica F. Boehler, Kristy J. Brown, Valeria Ricotti, Carl A. Morris
Multiple clinical trials to assess the efficacy of AAV-directed gene transfer in participants with Duchenne muscular dystrophy (DMD) are ongoing. The success of these trials currently relies on standard functional outcome measures that may exhibit variability within and between participants, rendering their use as sole measures of drug efficacy challenging. Given this, supportive objective biomarkers may be useful in enhancing observed clinical results. Creatine kinase (CK) is traditionally used as a diagnostic biomarker of DMD, but its potential as a robust pharmacodynamic (PD) biomarker is difficult due to the wide variability seen within the same participant over time. Thus, there is a need for the discovery and validation of novel PD biomarkers to further support and bolster traditional outcome measures of efficacy in DMD. Potential PD biomarkers in DMD participant urine were examined using a proteomic approach on the Somalogic platform. Findings were confirmed in both mdx mice and Golden Retriever muscular dystrophy (GRMD) dog plasma samples. Changes in the N-terminal fragment of titin, a well-known, previously characterized biomarker of DMD, were correlated with the expression of microdystrophin protein in mice, dogs, and humans. Further, titin levels were sensitive to lower levels of expressed microdystrophin when compared to CK. The measurement of objective PD biomarkers such as titin may provide additional confidence in the assessment of the mechanism of action and efficacy in gene therapy clinical trials of DMD. ClinicalTrials.gov NCT03368742.
{"title":"N-terminal titin fragment: a non-invasive, pharmacodynamic biomarker for microdystrophin efficacy","authors":"Jessica F. Boehler, Kristy J. Brown, Valeria Ricotti, Carl A. Morris","doi":"10.1186/s13395-023-00334-y","DOIUrl":"https://doi.org/10.1186/s13395-023-00334-y","url":null,"abstract":"Multiple clinical trials to assess the efficacy of AAV-directed gene transfer in participants with Duchenne muscular dystrophy (DMD) are ongoing. The success of these trials currently relies on standard functional outcome measures that may exhibit variability within and between participants, rendering their use as sole measures of drug efficacy challenging. Given this, supportive objective biomarkers may be useful in enhancing observed clinical results. Creatine kinase (CK) is traditionally used as a diagnostic biomarker of DMD, but its potential as a robust pharmacodynamic (PD) biomarker is difficult due to the wide variability seen within the same participant over time. Thus, there is a need for the discovery and validation of novel PD biomarkers to further support and bolster traditional outcome measures of efficacy in DMD. Potential PD biomarkers in DMD participant urine were examined using a proteomic approach on the Somalogic platform. Findings were confirmed in both mdx mice and Golden Retriever muscular dystrophy (GRMD) dog plasma samples. Changes in the N-terminal fragment of titin, a well-known, previously characterized biomarker of DMD, were correlated with the expression of microdystrophin protein in mice, dogs, and humans. Further, titin levels were sensitive to lower levels of expressed microdystrophin when compared to CK. The measurement of objective PD biomarkers such as titin may provide additional confidence in the assessment of the mechanism of action and efficacy in gene therapy clinical trials of DMD. ClinicalTrials.gov NCT03368742.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139476765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-03DOI: 10.1186/s13395-023-00329-9
Diego Jaime, Lauren A. Fish, Laura A. Madigan, Chengjie Xi, Giorgia Piccoli, Madison D. Ewing, Bert Blaauw, Justin R. Fallon
Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
{"title":"The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling","authors":"Diego Jaime, Lauren A. Fish, Laura A. Madigan, Chengjie Xi, Giorgia Piccoli, Madison D. Ewing, Bert Blaauw, Justin R. Fallon","doi":"10.1186/s13395-023-00329-9","DOIUrl":"https://doi.org/10.1186/s13395-023-00329-9","url":null,"abstract":"Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"53 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139082278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cross-sectional studies have demonstrated the association of skeletal muscle mass with metabolic-associated fatty liver disease (MAFLD), while longitudinal data are scarce. We aimed to explore the impact of changes in relative skeletal muscle mass on the MAFLD treatment response. MAFLD patients undergoing magnetic resonance imaging-based proton density fat fraction for liver fat content (LFC) assessments and bioelectrical impedance analysis before and after treatment (orlistat, meal replacement, lifestyle modifications) were enrolled. Appendicular muscle mass (ASM) was adjusted by weight (ASM/W). Overall, 256 participants were recruited and divided into two groups: with an ASM/W increase (n=166) and without an ASM/W increase (n=90). There was a great reduction in LFC in the group with an ASM/W increase (16.9% versus 8.2%, P < 0.001). However, the change in LFC in the group without an ASM/W increase showed no significant difference (12.5% versus 15.0%, P > 0.05). △ASM/W Follow-up-Baseline [odds ratio (OR)=1.48, 95% confidence interval (CI) 1.05-2.07, P = 0.024] and △total fat mass (OR=1.45, 95% CI 1.12-1.87, P = 0.004) were independent predictors for steatosis improvement (relative reduction of LFC ≥ 30%). The subgroup analysis showed that, despite without weight loss, decrease in HOMA-IR (OR=6.21, 95% CI 1.28-30.13, P=0.023), △total fat mass Baseline -Follow-up (OR=3.48, 95% CI 1.95-6.21, P <0.001 and △ASM/W Follow-up-Baseline (OR=2.13, 95% CI 1.12-4.05, P=0.022) independently predicted steatosis improvement. ASM/W increase and loss of total fat mass benefit the resolution of liver steatosis, independent of weight loss for MAFLD.
横断面研究表明，骨骼肌质量与代谢相关性脂肪肝（MAFLD）有关，但纵向数据却很少。我们旨在探索骨骼肌相对质量的变化对 MAFLD 治疗反应的影响。我们招募了在治疗（奥利司他、代餐、生活方式调整）前后接受基于磁共振成像的质子密度脂肪分数肝脏脂肪含量（LFC）评估和生物电阻抗分析的 MAFLD 患者。腓肠肌质量（ASM）根据体重（ASM/W）进行调整。总共招募了 256 名参与者，分为两组：ASM/W 增加组（166 人）和 ASM/W 未增加组（90 人）。ASM/W 增加组的 LFC 显著降低（16.9% 对 8.2%，P < 0.001）。然而，未提高 ASM/W 组的 LFC 变化无显著差异（12.5% 对 15.0%，P > 0.05）。△ASM/W随访-基线[几率比（OR）=1.48，95% 置信区间（CI）1.05-2.07，P = 0.024]和△总脂肪量（OR=1.45，95% CI 1.12-1.87，P = 0.004）是脂肪变性改善（LFC相对减少≥30%）的独立预测因素。亚组分析表明，尽管体重没有减轻，HOMA-IR的下降（OR=6.21，95% CI 1.28-30.13，P=0.023）、△总脂肪量基线-随访（OR=3.48，95% CI 1.95-6.21，P<0.001）和△ASM/W随访-基线（OR=2.13，95% CI 1.12-4.05，P=0.022）独立预测了脂肪变性的改善。ASM/W的增加和总脂肪量的减少有利于肝脏脂肪变性的缓解，与MAFLD的体重减轻无关。
{"title":"Restoring skeletal muscle mass as an independent determinant of liver fat deposition improvement in MAFLD","authors":"Ting Zhou, Junzhao Ye, Ling Luo, Wei Wang, Shiting Feng, Zhi Dong, Shuyu Zhuo, Bihui Zhong","doi":"10.1186/s13395-023-00333-z","DOIUrl":"https://doi.org/10.1186/s13395-023-00333-z","url":null,"abstract":"Cross-sectional studies have demonstrated the association of skeletal muscle mass with metabolic-associated fatty liver disease (MAFLD), while longitudinal data are scarce. We aimed to explore the impact of changes in relative skeletal muscle mass on the MAFLD treatment response. MAFLD patients undergoing magnetic resonance imaging-based proton density fat fraction for liver fat content (LFC) assessments and bioelectrical impedance analysis before and after treatment (orlistat, meal replacement, lifestyle modifications) were enrolled. Appendicular muscle mass (ASM) was adjusted by weight (ASM/W). Overall, 256 participants were recruited and divided into two groups: with an ASM/W increase (n=166) and without an ASM/W increase (n=90). There was a great reduction in LFC in the group with an ASM/W increase (16.9% versus 8.2%, P < 0.001). However, the change in LFC in the group without an ASM/W increase showed no significant difference (12.5% versus 15.0%, P > 0.05). △ASM/W Follow-up-Baseline [odds ratio (OR)=1.48, 95% confidence interval (CI) 1.05-2.07, P = 0.024] and △total fat mass (OR=1.45, 95% CI 1.12-1.87, P = 0.004) were independent predictors for steatosis improvement (relative reduction of LFC ≥ 30%). The subgroup analysis showed that, despite without weight loss, decrease in HOMA-IR (OR=6.21, 95% CI 1.28-30.13, P=0.023), △total fat mass Baseline -Follow-up (OR=3.48, 95% CI 1.95-6.21, P <0.001 and △ASM/W Follow-up-Baseline (OR=2.13, 95% CI 1.12-4.05, P=0.022) independently predicted steatosis improvement. ASM/W increase and loss of total fat mass benefit the resolution of liver steatosis, independent of weight loss for MAFLD.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"79 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138743524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol–treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.
{"title":"Eldecalcitol prevents muscle loss and osteoporosis in disuse muscle atrophy via NF-κB signaling in mice","authors":"Haichao Zhang, Yanping Du, Wenjing Tang, Minmin Chen, Weijia Yu, Zheng Ke, Shuangshuang Dong, Qun Cheng","doi":"10.1186/s13395-023-00332-0","DOIUrl":"https://doi.org/10.1186/s13395-023-00332-0","url":null,"abstract":"We investigated the effect of eldecalcitol on disuse muscle atrophy. C57BL/6J male mice aged 6 weeks were randomly assigned to control, tail suspension (TS), and TS-eldecalcitol–treated groups and were injected intraperitoneally twice a week with either vehicle (control and TS) or eldecalcitol at 3.5 or 5 ng for 3 weeks. Grip strength and muscle weights of the gastrocnemius (GAS), tibialis anterior (TA), and soleus (SOL) were determined. Oxidative stress was evaluated by malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase. Bone microarchitecture was analyzed using microcomputed tomography. The effect of eldecalcitol on C2C12 myoblasts was analyzed by measuring myofibrillar protein MHC and the atrophy markers Atrogin-1 and MuRF-1 using immunofluorescence. The influence of eldecalcitol on NF-κB signaling pathway and vitamin D receptor (VDR) was assessed through immunofluorescence, (co)-immunoprecipitation, and VDR knockdown studies. Eldecalcitol increased grip strength (P < 0.01) and restored muscle loss in GAS, TA, and SOL (P < 0.05 to P < 0.001) induced by TS. An improvement was noted in bone mineral density and bone architecture in the eldecalcitol group. The impaired oxidative defense system was restored by eldecalcitol (P < 0.05 to P < 0.01 vs. TS). Eldecalcitol (10 nM) significantly inhibited the expression of MuRF-1 (P < 0.001) and Atrogin-1 (P < 0.01), increased the diameter of myotubes (P < 0.05), inhibited the expression of P65 and P52 components of NF-κB and P65 nuclear location, thereby inhibiting NF-κB signaling. Eldecalcitol promoted VDR binding to P65 and P52. VDR signaling is required for eldecalcitol-mediated anti-atrophy effects. In conclusion, eldecalcitol exerted its beneficial effects on disuse-induced muscle atrophy via NF-κB inhibition.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"20 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138743519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-16DOI: 10.1186/s13395-023-00330-2
Thuy-Hang Nguyen, Lise Paprzycki, Alexandre Legrand, Anne-Emilie Declèves, Philipp Heher, Maelle Limpens, Alexandra Belayew, Christopher R. S. Banerji, Peter S. Zammit, Alexandra Tassin
Hypoxia is known to modify skeletal muscle biological functions and muscle regeneration. However, the mechanisms underlying the effects of hypoxia on human myoblast differentiation remain unclear. The hypoxic response pathway is of particular interest in patients with hereditary muscular dystrophies since many present respiratory impairment and muscle regeneration defects. For example, an altered hypoxia response characterizes the muscles of patients with facioscapulohumeral dystrophy (FSHD). We examined the impact of hypoxia on the differentiation of human immortalized myoblasts (LHCN-M2) cultured in normoxia (PO2: 21%) or hypoxia (PO2: 1%). Cells were grown in proliferation (myoblasts) or differentiation medium for 2 (myocytes) or 4 days (myotubes). We evaluated proliferation rate by EdU incorporation, used myogenin-positive nuclei as a differentiation marker for myocytes, and determined the fusion index and myosin heavy chain-positive area in myotubes. The contribution of HIF1α was studied by gain (CoCl2) and loss (siRNAs) of function experiments. We further examined hypoxia in LHCN-M2-iDUX4 myoblasts with inducible expression of DUX4, the transcription factor underlying FSHD pathology. We found that the hypoxic response did not impact myoblast proliferation but activated precocious myogenic differentiation and that HIF1α was critical for this process. Hypoxia also enhanced the late differentiation of human myocytes, but in an HIF1α-independent manner. Interestingly, the impact of hypoxia on muscle cell proliferation was influenced by dexamethasone. In the FSHD pathological context, DUX4 suppressed HIF1α-mediated precocious muscle differentiation. Hypoxia stimulates myogenic differentiation in healthy myoblasts, with HIF1α-dependent early steps. In FSHD, DUX4-HIF1α interplay indicates a novel mechanism by which DUX4 could interfere with HIF1α function in the myogenic program and therefore with FSHD muscle performance and regeneration.
众所周知，缺氧会改变骨骼肌的生物功能和肌肉再生。然而，低氧对人类成肌细胞分化的影响机制仍不清楚。遗传性肌肉萎缩症患者对低氧反应途径尤为关注，因为许多患者存在呼吸障碍和肌肉再生缺陷。例如，面岬肱肌营养不良症（FSHD）患者的肌肉就具有低氧反应改变的特征。我们研究了低氧对在常氧（PO2：21%）或低氧（PO2：1%）条件下培养的人类永生肌母细胞（LHCN-M2）分化的影响。细胞在增殖培养基（肌母细胞）或分化培养基中培养 2 天（肌细胞）或 4 天（肌管）。我们用 EdU 结合评估增殖率，用肌原蛋白阳性核作为肌细胞的分化标记，并测定肌管的融合指数和肌球蛋白重链阳性面积。通过功能增益（CoCl2）和功能缺失（siRNAs）实验研究了HIF1α的贡献。我们进一步研究了LHCN-M2-iDUX4肌母细胞的缺氧反应，这些肌母细胞诱导性表达了DUX4，DUX4是FSHD病理学的基础转录因子。我们发现，缺氧反应不会影响肌母细胞的增殖，但会激活早熟的肌原分化，而HIF1α对这一过程至关重要。缺氧也增强了人类肌细胞的后期分化，但其方式与 HIF1α 无关。有趣的是，低氧对肌肉细胞增殖的影响受到地塞米松的影响。在前列腺增生症的病理环境中，DUX4抑制了HIF1α介导的肌肉早熟分化。缺氧会刺激健康肌母细胞的成肌分化，其早期步骤依赖于 HIF1α。在前列腺增生症中，DUX4-HIF1α的相互作用表明了一种新的机制，通过这种机制，DUX4可以干扰肌生成程序中HIF1α的功能，从而影响前列腺增生症肌肉的性能和再生。
{"title":"Hypoxia enhances human myoblast differentiation: involvement of HIF1α and impact of DUX4, the FSHD causal gene","authors":"Thuy-Hang Nguyen, Lise Paprzycki, Alexandre Legrand, Anne-Emilie Declèves, Philipp Heher, Maelle Limpens, Alexandra Belayew, Christopher R. S. Banerji, Peter S. Zammit, Alexandra Tassin","doi":"10.1186/s13395-023-00330-2","DOIUrl":"https://doi.org/10.1186/s13395-023-00330-2","url":null,"abstract":"Hypoxia is known to modify skeletal muscle biological functions and muscle regeneration. However, the mechanisms underlying the effects of hypoxia on human myoblast differentiation remain unclear. The hypoxic response pathway is of particular interest in patients with hereditary muscular dystrophies since many present respiratory impairment and muscle regeneration defects. For example, an altered hypoxia response characterizes the muscles of patients with facioscapulohumeral dystrophy (FSHD). We examined the impact of hypoxia on the differentiation of human immortalized myoblasts (LHCN-M2) cultured in normoxia (PO2: 21%) or hypoxia (PO2: 1%). Cells were grown in proliferation (myoblasts) or differentiation medium for 2 (myocytes) or 4 days (myotubes). We evaluated proliferation rate by EdU incorporation, used myogenin-positive nuclei as a differentiation marker for myocytes, and determined the fusion index and myosin heavy chain-positive area in myotubes. The contribution of HIF1α was studied by gain (CoCl2) and loss (siRNAs) of function experiments. We further examined hypoxia in LHCN-M2-iDUX4 myoblasts with inducible expression of DUX4, the transcription factor underlying FSHD pathology. We found that the hypoxic response did not impact myoblast proliferation but activated precocious myogenic differentiation and that HIF1α was critical for this process. Hypoxia also enhanced the late differentiation of human myocytes, but in an HIF1α-independent manner. Interestingly, the impact of hypoxia on muscle cell proliferation was influenced by dexamethasone. In the FSHD pathological context, DUX4 suppressed HIF1α-mediated precocious muscle differentiation. Hypoxia stimulates myogenic differentiation in healthy myoblasts, with HIF1α-dependent early steps. In FSHD, DUX4-HIF1α interplay indicates a novel mechanism by which DUX4 could interfere with HIF1α function in the myogenic program and therefore with FSHD muscle performance and regeneration.","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"51 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2023-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138686794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-04DOI: 10.1186/s13395-023-00328-w
Déborah Cardoso, Inès Barthélémy, Stéphane Blot, Antoine Muchir
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene and loss of the protein dystrophin, which ultimately leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Among the developed therapeutic strategies for DMD, gene therapy approaches partially restore micro-dystrophin or quasi-dystrophin expression. However, despite extensive attempts to develop definitive therapies for DMD, the standard of care remains corticosteroid, which has only palliative benefits. Animal models have played a key role in studies of DMD pathogenesis and treatment development. The golden retriever muscular dystrophy (GRMD) dog displays a phenotype aligning with the progressive course of DMD. Therefore, canine studies may translate better to humans. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for striated muscle function. We showed here that NAD+ content was decreased in the striated muscles of GRMD, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Moreover, we showed that boosting NAD+ content using nicotinamide (NAM), a natural NAD+ precursor, modestly reduces aspects of striated muscle disease. Collectively, our results provide mechanistic insights into DMD.
{"title":"Replenishing NAD<sup>+</sup> content reduces aspects of striated muscle disease in a dog model of Duchenne muscular dystrophy.","authors":"Déborah Cardoso, Inès Barthélémy, Stéphane Blot, Antoine Muchir","doi":"10.1186/s13395-023-00328-w","DOIUrl":"10.1186/s13395-023-00328-w","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene and loss of the protein dystrophin, which ultimately leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Among the developed therapeutic strategies for DMD, gene therapy approaches partially restore micro-dystrophin or quasi-dystrophin expression. However, despite extensive attempts to develop definitive therapies for DMD, the standard of care remains corticosteroid, which has only palliative benefits. Animal models have played a key role in studies of DMD pathogenesis and treatment development. The golden retriever muscular dystrophy (GRMD) dog displays a phenotype aligning with the progressive course of DMD. Therefore, canine studies may translate better to humans. Recent studies suggested that nicotinamide adenine dinucleotide (NAD<sup>+</sup>) cellular content could be a critical determinant for striated muscle function. We showed here that NAD<sup>+</sup> content was decreased in the striated muscles of GRMD, leading to an alteration of one of NAD<sup>+</sup> co-substrate enzymes, PARP-1. Moreover, we showed that boosting NAD<sup>+</sup> content using nicotinamide (NAM), a natural NAD<sup>+</sup> precursor, modestly reduces aspects of striated muscle disease. Collectively, our results provide mechanistic insights into DMD.</p>","PeriodicalId":21747,"journal":{"name":"Skeletal Muscle","volume":"13 1","pages":"20"},"PeriodicalIF":4.9,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10694913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478455","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}
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