A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data

Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Zhihao Xie [verfasserIn] Chang Liu [verfasserIn] Chengyue Sun [verfasserIn] Yanyu Lu [verfasserIn] Shiyi Wu [verfasserIn] Yilin Liu [verfasserIn] Qi Wang [verfasserIn] Yalan Wan [verfasserIn] Yikang Wang [verfasserIn] Meng Yu [verfasserIn] Lingchao Meng [verfasserIn] Jianwen Deng [verfasserIn] Wei Zhang [verfasserIn] Zhaoxia Wang [verfasserIn] Chunxia Yang [verfasserIn] Yun Yuan [verfasserIn] Zhiying Xie [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome

Übergeordnetes Werk:	In: Journal of Cachexia, Sarcopenia and Muscle - Wiley, 2016, 15(2024), 1, Seite 98-111
Übergeordnetes Werk:	volume:15 ; year:2024 ; number:1 ; pages:98-111

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.1002/jcsm.13410

Katalog-ID:	DOAJ095985212

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520			\|a Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.
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650		4	\|a Duchenne muscular dystrophy
650		4	\|a Fibrofatty replacement
650		4	\|a Transcriptome
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700	0		\|a Shiyi Wu \|e verfasserin \|4 aut
700	0		\|a Yilin Liu \|e verfasserin \|4 aut
700	0		\|a Qi Wang \|e verfasserin \|4 aut
700	0		\|a Yalan Wan \|e verfasserin \|4 aut
700	0		\|a Yikang Wang \|e verfasserin \|4 aut
700	0		\|a Meng Yu \|e verfasserin \|4 aut
700	0		\|a Lingchao Meng \|e verfasserin \|4 aut
700	0		\|a Jianwen Deng \|e verfasserin \|4 aut
700	0		\|a Wei Zhang \|e verfasserin \|4 aut
700	0		\|a Zhaoxia Wang \|e verfasserin \|4 aut
700	0		\|a Chunxia Yang \|e verfasserin \|4 aut
700	0		\|a Yun Yuan \|e verfasserin \|4 aut
700	0		\|a Zhiying Xie \|e verfasserin \|4 aut
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allfields	10.1002/jcsm.13410 doi (DE-627)DOAJ095985212 (DE-599)DOAJfa65f1eaa6a34093b993df6f469c9b0f DE-627 ger DE-627 rakwb eng RC925-935 QM1-695 Zhihao Xie verfasserin aut A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies. Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome Diseases of the musculoskeletal system Human anatomy Chang Liu verfasserin aut Chengyue Sun verfasserin aut Yanyu Lu verfasserin aut Shiyi Wu verfasserin aut Yilin Liu verfasserin aut Qi Wang verfasserin aut Yalan Wan verfasserin aut Yikang Wang verfasserin aut Meng Yu verfasserin aut Lingchao Meng verfasserin aut Jianwen Deng verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Chunxia Yang verfasserin aut Yun Yuan verfasserin aut Zhiying Xie verfasserin aut In Journal of Cachexia, Sarcopenia and Muscle Wiley, 2016 15(2024), 1, Seite 98-111 (DE-627)642886121 (DE-600)2586864-0 21906009 nnns volume:15 year:2024 number:1 pages:98-111 https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/article/fa65f1eaa6a34093b993df6f469c9b0f kostenfrei https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/toc/2190-5991 Journal toc kostenfrei https://doaj.org/toc/2190-6009 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 98-111
spelling	10.1002/jcsm.13410 doi (DE-627)DOAJ095985212 (DE-599)DOAJfa65f1eaa6a34093b993df6f469c9b0f DE-627 ger DE-627 rakwb eng RC925-935 QM1-695 Zhihao Xie verfasserin aut A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies. Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome Diseases of the musculoskeletal system Human anatomy Chang Liu verfasserin aut Chengyue Sun verfasserin aut Yanyu Lu verfasserin aut Shiyi Wu verfasserin aut Yilin Liu verfasserin aut Qi Wang verfasserin aut Yalan Wan verfasserin aut Yikang Wang verfasserin aut Meng Yu verfasserin aut Lingchao Meng verfasserin aut Jianwen Deng verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Chunxia Yang verfasserin aut Yun Yuan verfasserin aut Zhiying Xie verfasserin aut In Journal of Cachexia, Sarcopenia and Muscle Wiley, 2016 15(2024), 1, Seite 98-111 (DE-627)642886121 (DE-600)2586864-0 21906009 nnns volume:15 year:2024 number:1 pages:98-111 https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/article/fa65f1eaa6a34093b993df6f469c9b0f kostenfrei https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/toc/2190-5991 Journal toc kostenfrei https://doaj.org/toc/2190-6009 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 98-111
allfields_unstemmed	10.1002/jcsm.13410 doi (DE-627)DOAJ095985212 (DE-599)DOAJfa65f1eaa6a34093b993df6f469c9b0f DE-627 ger DE-627 rakwb eng RC925-935 QM1-695 Zhihao Xie verfasserin aut A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies. Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome Diseases of the musculoskeletal system Human anatomy Chang Liu verfasserin aut Chengyue Sun verfasserin aut Yanyu Lu verfasserin aut Shiyi Wu verfasserin aut Yilin Liu verfasserin aut Qi Wang verfasserin aut Yalan Wan verfasserin aut Yikang Wang verfasserin aut Meng Yu verfasserin aut Lingchao Meng verfasserin aut Jianwen Deng verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Chunxia Yang verfasserin aut Yun Yuan verfasserin aut Zhiying Xie verfasserin aut In Journal of Cachexia, Sarcopenia and Muscle Wiley, 2016 15(2024), 1, Seite 98-111 (DE-627)642886121 (DE-600)2586864-0 21906009 nnns volume:15 year:2024 number:1 pages:98-111 https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/article/fa65f1eaa6a34093b993df6f469c9b0f kostenfrei https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/toc/2190-5991 Journal toc kostenfrei https://doaj.org/toc/2190-6009 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 98-111
allfieldsGer	10.1002/jcsm.13410 doi (DE-627)DOAJ095985212 (DE-599)DOAJfa65f1eaa6a34093b993df6f469c9b0f DE-627 ger DE-627 rakwb eng RC925-935 QM1-695 Zhihao Xie verfasserin aut A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies. Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome Diseases of the musculoskeletal system Human anatomy Chang Liu verfasserin aut Chengyue Sun verfasserin aut Yanyu Lu verfasserin aut Shiyi Wu verfasserin aut Yilin Liu verfasserin aut Qi Wang verfasserin aut Yalan Wan verfasserin aut Yikang Wang verfasserin aut Meng Yu verfasserin aut Lingchao Meng verfasserin aut Jianwen Deng verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Chunxia Yang verfasserin aut Yun Yuan verfasserin aut Zhiying Xie verfasserin aut In Journal of Cachexia, Sarcopenia and Muscle Wiley, 2016 15(2024), 1, Seite 98-111 (DE-627)642886121 (DE-600)2586864-0 21906009 nnns volume:15 year:2024 number:1 pages:98-111 https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/article/fa65f1eaa6a34093b993df6f469c9b0f kostenfrei https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/toc/2190-5991 Journal toc kostenfrei https://doaj.org/toc/2190-6009 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 98-111
allfieldsSound	10.1002/jcsm.13410 doi (DE-627)DOAJ095985212 (DE-599)DOAJfa65f1eaa6a34093b993df6f469c9b0f DE-627 ger DE-627 rakwb eng RC925-935 QM1-695 Zhihao Xie verfasserin aut A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies. Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome Diseases of the musculoskeletal system Human anatomy Chang Liu verfasserin aut Chengyue Sun verfasserin aut Yanyu Lu verfasserin aut Shiyi Wu verfasserin aut Yilin Liu verfasserin aut Qi Wang verfasserin aut Yalan Wan verfasserin aut Yikang Wang verfasserin aut Meng Yu verfasserin aut Lingchao Meng verfasserin aut Jianwen Deng verfasserin aut Wei Zhang verfasserin aut Zhaoxia Wang verfasserin aut Chunxia Yang verfasserin aut Yun Yuan verfasserin aut Zhiying Xie verfasserin aut In Journal of Cachexia, Sarcopenia and Muscle Wiley, 2016 15(2024), 1, Seite 98-111 (DE-627)642886121 (DE-600)2586864-0 21906009 nnns volume:15 year:2024 number:1 pages:98-111 https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/article/fa65f1eaa6a34093b993df6f469c9b0f kostenfrei https://doi.org/10.1002/jcsm.13410 kostenfrei https://doaj.org/toc/2190-5991 Journal toc kostenfrei https://doaj.org/toc/2190-6009 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 98-111
language	English
source	In Journal of Cachexia, Sarcopenia and Muscle 15(2024), 1, Seite 98-111 volume:15 year:2024 number:1 pages:98-111
sourceStr	In Journal of Cachexia, Sarcopenia and Muscle 15(2024), 1, Seite 98-111 volume:15 year:2024 number:1 pages:98-111
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome Diseases of the musculoskeletal system Human anatomy
isfreeaccess_bool	true
container_title	Journal of Cachexia, Sarcopenia and Muscle
authorswithroles_txt_mv	Zhihao Xie @@aut@@ Chang Liu @@aut@@ Chengyue Sun @@aut@@ Yanyu Lu @@aut@@ Shiyi Wu @@aut@@ Yilin Liu @@aut@@ Qi Wang @@aut@@ Yalan Wan @@aut@@ Yikang Wang @@aut@@ Meng Yu @@aut@@ Lingchao Meng @@aut@@ Jianwen Deng @@aut@@ Wei Zhang @@aut@@ Zhaoxia Wang @@aut@@ Chunxia Yang @@aut@@ Yun Yuan @@aut@@ Zhiying Xie @@aut@@
publishDateDaySort_date	2024-01-01T00:00:00Z
hierarchy_top_id	642886121
id	DOAJ095985212
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">DOAJ095985212</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20240413135234.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">240413s2024 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1002/jcsm.13410</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ095985212</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJfa65f1eaa6a34093b993df6f469c9b0f</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC925-935</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">QM1-695</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Zhihao Xie</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="2"><subfield code="a">A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2024</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Becker muscular dystrophy</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Duchenne muscular dystrophy</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Fibrofatty replacement</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Transcriptome</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Diseases of the musculoskeletal system</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Human anatomy</subfield></datafield><datafield tag="700" ind1="0" ind2=" "><subfield code="a">Chang Liu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" 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callnumber-first	R - Medicine
author	Zhihao Xie
spellingShingle	Zhihao Xie misc RC925-935 misc QM1-695 misc Becker muscular dystrophy misc Duchenne muscular dystrophy misc Fibrofatty replacement misc Transcriptome misc Diseases of the musculoskeletal system misc Human anatomy A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
authorStr	Zhihao Xie
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topic_title	RC925-935 QM1-695 A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data Becker muscular dystrophy Duchenne muscular dystrophy Fibrofatty replacement Transcriptome
topic	misc RC925-935 misc QM1-695 misc Becker muscular dystrophy misc Duchenne muscular dystrophy misc Fibrofatty replacement misc Transcriptome misc Diseases of the musculoskeletal system misc Human anatomy
topic_unstemmed	misc RC925-935 misc QM1-695 misc Becker muscular dystrophy misc Duchenne muscular dystrophy misc Fibrofatty replacement misc Transcriptome misc Diseases of the musculoskeletal system misc Human anatomy
topic_browse	misc RC925-935 misc QM1-695 misc Becker muscular dystrophy misc Duchenne muscular dystrophy misc Fibrofatty replacement misc Transcriptome misc Diseases of the musculoskeletal system misc Human anatomy
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title	A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
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title_full	A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
author_sort	Zhihao Xie
journal	Journal of Cachexia, Sarcopenia and Muscle
journalStr	Journal of Cachexia, Sarcopenia and Muscle
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author_browse	Zhihao Xie Chang Liu Chengyue Sun Yanyu Lu Shiyi Wu Yilin Liu Qi Wang Yalan Wan Yikang Wang Meng Yu Lingchao Meng Jianwen Deng Wei Zhang Zhaoxia Wang Chunxia Yang Yun Yuan Zhiying Xie
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title_sort	novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
callnumber	RC925-935
title_auth	A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
abstract	Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.
abstractGer	Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.
abstract_unstemmed	Abstract Background We aimed to analyse genome‐wide transcriptome differences between Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients and identify biomarkers that correlate well with muscle magnetic resonance imaging (MRI) and histological fibrofatty replacement in both patients, which have not been reported. Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. Conclusions We identify CDKN2A expression as a novel biomarker of fibrofatty replacement, which might be a new target for antifibrotic therapy in dystrophinopathies.
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container_issue	1
title_short	A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data
url	https://doi.org/10.1002/jcsm.13410 https://doaj.org/article/fa65f1eaa6a34093b993df6f469c9b0f https://doaj.org/toc/2190-5991 https://doaj.org/toc/2190-6009
remote_bool	true
author2	Chang Liu Chengyue Sun Yanyu Lu Shiyi Wu Yilin Liu Qi Wang Yalan Wan Yikang Wang Meng Yu Lingchao Meng Jianwen Deng Wei Zhang Zhaoxia Wang Chunxia Yang Yun Yuan Zhiying Xie
author2Str	Chang Liu Chengyue Sun Yanyu Lu Shiyi Wu Yilin Liu Qi Wang Yalan Wan Yikang Wang Meng Yu Lingchao Meng Jianwen Deng Wei Zhang Zhaoxia Wang Chunxia Yang Yun Yuan Zhiying Xie
ppnlink	642886121
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doi_str	10.1002/jcsm.13410
callnumber-a	RC925-935
up_date	2024-07-03T17:43:42.546Z
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Methods One hundred and one male patients with dystrophinopathies (55 DMD and 46 BMD) were enrolled. Muscle‐derived genome‐wide RNA‐sequencing was performed in 31 DMD patients, 29 BMD patients, and 11 normal controls. Fibrofatty replacement was scored on muscle MRI and histological levels in all patients. A unique pipeline, single‐sample gene set enrichment analysis combined with Spearman's rank correlations (ssGSEA‐Cor) was developed to identify the most correlated gene signature for fibrofatty replacement. Quantitative real‐time PCR (qRT‐PCR) analysis, western blot analysis, and single‐nucleus RNA‐sequencing (snRNA‐seq) were performed in the remaining patients to validate the most correlated gene signature. Results Comparative transcriptomic analysis revealed that 31 DMD muscles were characterized by a significant increase of inflammation/immune response and extracellular matrix remodelling compared with 29 BMD muscles (P < 0.05). The ssGSEA‐Cor pipeline revealed that the gene set of CDKN2A and CDKN2B was the most correlated gene signature for fibrofatty replacement (histological rs = 0.744, P < 0.001; MRI rs = 0.718, P < 0.001). Muscle qRT‐PCR confirmed that CDKN2A mRNA expression in both 15 DMD (median = 25.007, P < 0.001) and 12 BMD (median = 5.654, P < 0.001) patients were significantly higher than that in controls (median = 1.101), while no significant difference in CDKN2B mRNA expression was found among DMD, BMD, and control groups. In the 27 patients, muscle CDKN2A mRNA expression respectively correlated with muscle MRI (rs = 0.883, P < 0.001) and histological fibrofatty replacement (rs = 0.804, P < 0.001) and disease duration (rs = 0.645, P < 0.001) and North Star Ambulatory Assessment total scores (rs = −0.698, P < 0.001). Muscle western blot analysis confirmed that both four DMD (median = 2.958, P < 0.05) and four BMD (median = 1.959, P < 0.01) patients had a significantly higher level of CDKN2A protein expression than controls (median = 1.068). The snRNA‐seq analysis of two DMD muscles revealed that CDKN2A was mainly expressed in fibro‐adipogenic progenitors, satellite cells, and myoblasts. 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A novel biomarker of fibrofatty replacement in dystrophinopathies identified by integrating transcriptome, magnetic resonance imaging, and pathology data

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