Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease
Abstract Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and percussion-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently, we identified cavin 4...
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BMC
2025-01-01
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| Series: | Acta Neuropathologica Communications |
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| Online Access: | https://doi.org/10.1186/s40478-025-01926-z |
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| author | Samir R. Nath Aneesha Dasgupta Divyanshu Dubey Eileen Kokesh Grayson Beecher Numrah Fadra Teerin Liewluck Sean Pittock Jason D. Doles William Litchy Margherita Milone |
| author_facet | Samir R. Nath Aneesha Dasgupta Divyanshu Dubey Eileen Kokesh Grayson Beecher Numrah Fadra Teerin Liewluck Sean Pittock Jason D. Doles William Litchy Margherita Milone |
| author_sort | Samir R. Nath |
| collection | DOAJ |
| description | Abstract Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and percussion-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently, we identified cavin 4 autoantibodies as a biomarker of immune-mediated RMD (iRMD), though the underlying disease-mechanisms remain poorly understood. Transcriptomic studies were performed on muscle biopsies of 8 patients (5 males; 3 females; ages 26-to-80) with iRMD. Subsequent pathway analysis compared iRMD to human non-disease control and disease control (dermatomyositis) muscle samples. Transcriptomic studies demonstrated changes in key pathways of muscle contraction and development. All iRMD samples had significantly upregulated cavin-4 expression compared to controls, likely compensatory for autoantibody-mediated protein degradation. Proteins involved in muscle relaxation (including SERCA1, PMCA and PLN) were significantly increased in iRMD compared to controls. Comparison of iRMD to dermatomyositis transcriptomics demonstrated significant overlap in immune pathways, and the IL-6 signaling pathway was markedly increased in all iRMD patient muscle biopsies and increased in the majority of iRMD patients’ serum. This study represents the first muscle transcriptomic analysis of iRMD patients and dissects underlying disease mechanisms. Increase of sarcolemmal and cellular calcium channels as well as PLN, an inhibitor of the SERCA pump for calcium into the sarcoplasm, likely alters the calcium dynamics in iRMD. These changes in crucial components of muscle relaxation may underlie rippling by altering calcium flux. Our findings provide crucial insights into the differential expression of genes regulating muscle relaxation and highlight potential disease pathomechanisms. |
| format | Article |
| id | doaj-art-3d1f72589fb340a3805f15b35dbf81ae |
| institution | DOAJ |
| issn | 2051-5960 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj-art-3d1f72589fb340a3805f15b35dbf81ae2025-08-20T02:49:12ZengBMCActa Neuropathologica Communications2051-59602025-01-0113111310.1186/s40478-025-01926-zUnraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle diseaseSamir R. Nath0Aneesha Dasgupta1Divyanshu Dubey2Eileen Kokesh3Grayson Beecher4Numrah Fadra5Teerin Liewluck6Sean Pittock7Jason D. Doles8William Litchy9Margherita Milone10Department of Neurology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDivision of Computational Biology, Department of Quantitative Health Sciences Research, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Neurology, Mayo ClinicDepartment of Neurology, Mayo ClinicAbstract Rippling Muscle Disease (RMD) is a rare skeletal myopathy characterized by abnormal muscular excitability manifesting with wave-like muscle contractions and percussion-induced muscle mounding. Hereditary RMD is associated with caveolin-3 or cavin-1 mutations. Recently, we identified cavin 4 autoantibodies as a biomarker of immune-mediated RMD (iRMD), though the underlying disease-mechanisms remain poorly understood. Transcriptomic studies were performed on muscle biopsies of 8 patients (5 males; 3 females; ages 26-to-80) with iRMD. Subsequent pathway analysis compared iRMD to human non-disease control and disease control (dermatomyositis) muscle samples. Transcriptomic studies demonstrated changes in key pathways of muscle contraction and development. All iRMD samples had significantly upregulated cavin-4 expression compared to controls, likely compensatory for autoantibody-mediated protein degradation. Proteins involved in muscle relaxation (including SERCA1, PMCA and PLN) were significantly increased in iRMD compared to controls. Comparison of iRMD to dermatomyositis transcriptomics demonstrated significant overlap in immune pathways, and the IL-6 signaling pathway was markedly increased in all iRMD patient muscle biopsies and increased in the majority of iRMD patients’ serum. This study represents the first muscle transcriptomic analysis of iRMD patients and dissects underlying disease mechanisms. Increase of sarcolemmal and cellular calcium channels as well as PLN, an inhibitor of the SERCA pump for calcium into the sarcoplasm, likely alters the calcium dynamics in iRMD. These changes in crucial components of muscle relaxation may underlie rippling by altering calcium flux. Our findings provide crucial insights into the differential expression of genes regulating muscle relaxation and highlight potential disease pathomechanisms.https://doi.org/10.1186/s40478-025-01926-zImmune mediated rippling muscle diseaseMyopathyTranscriptomicsInterleukin-6Interferon |
| spellingShingle | Samir R. Nath Aneesha Dasgupta Divyanshu Dubey Eileen Kokesh Grayson Beecher Numrah Fadra Teerin Liewluck Sean Pittock Jason D. Doles William Litchy Margherita Milone Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease Acta Neuropathologica Communications Immune mediated rippling muscle disease Myopathy Transcriptomics Interleukin-6 Interferon |
| title | Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease |
| title_full | Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease |
| title_fullStr | Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease |
| title_full_unstemmed | Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease |
| title_short | Unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease |
| title_sort | unraveling calcium dysregulation and autoimmunity in immune mediated rippling muscle disease |
| topic | Immune mediated rippling muscle disease Myopathy Transcriptomics Interleukin-6 Interferon |
| url | https://doi.org/10.1186/s40478-025-01926-z |
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