Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy
Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This stu...
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| description | Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy. We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy. A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM. |
| doi_str_mv | 10.1186/s12864-021-07758-0 |
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In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy. We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy. A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.</description><identifier>ISSN: 1471-2164</identifier><identifier>EISSN: 1471-2164</identifier><identifier>DOI: 10.1186/s12864-021-07758-0</identifier><identifier>PMID: 34112090</identifier><language>eng</language><publisher>London: BioMed Central Ltd</publisher><subject>Agglomeration ; Amalgamation ; Apoptosis ; Atrophy ; Biomarkers ; Cristae ; Degeneration ; Desmin ; Disease ; Diseases ; Electron microscopy ; Electron transport chain ; Extracellular matrix ; Gene expression ; Gene sequencing ; Genetic aspects ; Genomes ; Genomics ; Glutathione ; Gluteal muscle ; Health aspects ; Horses ; Laboratory animals ; Methods ; Mitochondria ; Muscles ; Mutation ; Myofibrillar myopathy ; Myopathy ; NADH-ubiquinone oxidoreductase ; Neuromuscular diseases ; Oxidative stress ; Pathophysiology ; Protein interaction ; Protein-protein interactions ; Proteins ; Proteomics ; RNA sequencing ; Signaling ; Skeletal muscle ; Striated muscle ; Transcription ; Transcriptomics ; Warmblood ; Z-disc</subject><ispartof>BMC genomics, 2021-06, Vol.22 (1), p.1-438, Article 438</ispartof><rights>COPYRIGHT 2021 BioMed Central Ltd.</rights><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c501t-dfb025b72135eae82d72cffe504795e1516575a7888ec0e066bca312a4b6d5a73</citedby><cites>FETCH-LOGICAL-c501t-dfb025b72135eae82d72cffe504795e1516575a7888ec0e066bca312a4b6d5a73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194174/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194174/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,27901,27902,53766,53768</link.rule.ids></links><search><creatorcontrib>Williams, Zoë J.</creatorcontrib><creatorcontrib>Velez-Irizarry, Deborah</creatorcontrib><creatorcontrib>Gardner, Keri</creatorcontrib><creatorcontrib>Valberg, Stephanie J.</creatorcontrib><title>Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy</title><title>BMC genomics</title><description>Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy. We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy. A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.</description><subject>Agglomeration</subject><subject>Amalgamation</subject><subject>Apoptosis</subject><subject>Atrophy</subject><subject>Biomarkers</subject><subject>Cristae</subject><subject>Degeneration</subject><subject>Desmin</subject><subject>Disease</subject><subject>Diseases</subject><subject>Electron microscopy</subject><subject>Electron transport chain</subject><subject>Extracellular matrix</subject><subject>Gene expression</subject><subject>Gene sequencing</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Glutathione</subject><subject>Gluteal muscle</subject><subject>Health aspects</subject><subject>Horses</subject><subject>Laboratory animals</subject><subject>Methods</subject><subject>Mitochondria</subject><subject>Muscles</subject><subject>Mutation</subject><subject>Myofibrillar myopathy</subject><subject>Myopathy</subject><subject>NADH-ubiquinone oxidoreductase</subject><subject>Neuromuscular diseases</subject><subject>Oxidative stress</subject><subject>Pathophysiology</subject><subject>Protein interaction</subject><subject>Protein-protein interactions</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>RNA sequencing</subject><subject>Signaling</subject><subject>Skeletal muscle</subject><subject>Striated muscle</subject><subject>Transcription</subject><subject>Transcriptomics</subject><subject>Warmblood</subject><subject>Z-disc</subject><issn>1471-2164</issn><issn>1471-2164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNpdkk1v1DAQhiMEoqXwBzhZ4sKhAduJP3JBqio-VqrEBcTRcpxJ4lViB9sLu_-Un4OTrYBysv3O62fG4ymKlwS_IUTyt5FQyesSU1JiIZgs8aPiktSClJTw-vE_-4viWYx7jImQlD0tLqqaEIobfFn82rkEQ9AJOrQEn8DP1iDtOpSCdtEEu6RNysHeTtYNyHbgku0tRKRbCNmW0AAOtlsbwzoExyVAjNY7lE9pBBR1MH6GANdotsmb0bsuWD2hrC4THNHu-pw3e-GYsxuYpsOkA5p1Cva4cr7pMLeT9x0afYi5gJ82jWg-5dLaYKfNfPKLTuPpefGk11OEF_frVfH1w_svt5_Ku88fd7c3d6VhmKSy61tMWSsoqRhokLQT1PQ9MFyLhgFhhDPBtJBSgsGAOW-NrgjVdcu7rFdXxe7M7bzeqyXYWYeT8tqqTfBhUDokayZQktDMkBwLaGrSYY2hNoT3EvOGmabKrHdn1nJoZ-hM7nPQ0wPow4izoxr8j0zOQFFnwOt7QPDfDxCTmm1c-6gd-ENUlNWYEVk1Tba--s-694fgcqtWV5Wb00jy1zXo_ADrer9-zApVN5yzmrKGrix6dpngYwzQ_ymZYLWOqjqPqsqjqrZRVbj6DVW64Ec</recordid><startdate>20210611</startdate><enddate>20210611</enddate><creator>Williams, 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proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy</title><author>Williams, Zoë J. ; Velez-Irizarry, Deborah ; Gardner, Keri ; Valberg, Stephanie J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c501t-dfb025b72135eae82d72cffe504795e1516575a7888ec0e066bca312a4b6d5a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Agglomeration</topic><topic>Amalgamation</topic><topic>Apoptosis</topic><topic>Atrophy</topic><topic>Biomarkers</topic><topic>Cristae</topic><topic>Degeneration</topic><topic>Desmin</topic><topic>Disease</topic><topic>Diseases</topic><topic>Electron microscopy</topic><topic>Electron transport chain</topic><topic>Extracellular matrix</topic><topic>Gene expression</topic><topic>Gene sequencing</topic><topic>Genetic aspects</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Glutathione</topic><topic>Gluteal muscle</topic><topic>Health aspects</topic><topic>Horses</topic><topic>Laboratory animals</topic><topic>Methods</topic><topic>Mitochondria</topic><topic>Muscles</topic><topic>Mutation</topic><topic>Myofibrillar myopathy</topic><topic>Myopathy</topic><topic>NADH-ubiquinone oxidoreductase</topic><topic>Neuromuscular diseases</topic><topic>Oxidative stress</topic><topic>Pathophysiology</topic><topic>Protein interaction</topic><topic>Protein-protein interactions</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>RNA sequencing</topic><topic>Signaling</topic><topic>Skeletal muscle</topic><topic>Striated muscle</topic><topic>Transcription</topic><topic>Transcriptomics</topic><topic>Warmblood</topic><topic>Z-disc</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Williams, Zoë 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Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>BMC genomics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Williams, Zoë J.</au><au>Velez-Irizarry, Deborah</au><au>Gardner, Keri</au><au>Valberg, Stephanie J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy</atitle><jtitle>BMC genomics</jtitle><date>2021-06-11</date><risdate>2021</risdate><volume>22</volume><issue>1</issue><spage>1</spage><epage>438</epage><pages>1-438</pages><artnum>438</artnum><issn>1471-2164</issn><eissn>1471-2164</eissn><abstract>Myofibrillar myopathy in humans causes protein aggregation, degeneration, and weakness of skeletal muscle. In horses, myofibrillar myopathy is a late-onset disease of unknown origin characterized by poor performance, atrophy, myofibrillar disarray, and desmin aggregation in skeletal muscle. This study evaluated molecular and ultrastructural signatures of myofibrillar myopathy in Warmblood horses through gluteal muscle tandem-mass-tag quantitative proteomics (5 affected, 4 control), mRNA-sequencing (8 affected, 8 control), amalgamated gene ontology analyses, and immunofluorescent and electron microscopy. We identified 93/1533 proteins and 47/27,690 genes that were significantly differentially expressed. The top significantly differentially expressed protein CSRP3 and three other differentially expressed proteins, including, PDLIM3, SYNPO2, and SYNPOL2, are integrally involved in Z-disc signaling, gene transcription and subsequently sarcomere integrity. Through immunofluorescent staining, both desmin aggregates and CSRP3 were localized to type 2A fibers. The highest differentially expressed gene CHAC1, whose protein product degrades glutathione, is associated with oxidative stress and apoptosis. Amalgamated transcriptomic and proteomic gene ontology analyses identified 3 enriched cellular locations; the sarcomere (Z-disc & I-band), mitochondrial complex I and the extracellular matrix which corresponded to ultrastructural Z-disc disruption and mitochondrial cristae alterations found with electron microscopy. A combined proteomic and transcriptomic analysis highlighted three enriched cellular locations that correspond with MFM ultrastructural pathology in Warmblood horses. Aberrant Z-disc mechano-signaling, impaired Z-disc stability, decreased mitochondrial complex I expression, and a pro-oxidative cellular environment are hypothesized to contribute to the development of myofibrillar myopathy in Warmblood horses. These molecular signatures may provide further insight into diagnostic biomarkers, treatments, and the underlying pathophysiology of MFM.</abstract><cop>London</cop><pub>BioMed Central Ltd</pub><pmid>34112090</pmid><doi>10.1186/s12864-021-07758-0</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Agglomeration Amalgamation Apoptosis Atrophy Biomarkers Cristae Degeneration Desmin Disease Diseases Electron microscopy Electron transport chain Extracellular matrix Gene expression Gene sequencing Genetic aspects Genomes Genomics Glutathione Gluteal muscle Health aspects Horses Laboratory animals Methods Mitochondria Muscles Mutation Myofibrillar myopathy Myopathy NADH-ubiquinone oxidoreductase Neuromuscular diseases Oxidative stress Pathophysiology Protein interaction Protein-protein interactions Proteins Proteomics RNA sequencing Signaling Skeletal muscle Striated muscle Transcription Transcriptomics Warmblood Z-disc |
| title | Integrated proteomic and transcriptomic profiling identifies aberrant gene and protein expression in the sarcomere, mitochondrial complex I, and the extracellular matrix in Warmblood horses with myofibrillar myopathy |
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