Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits
Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common...
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| Format: | Article |
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MDPI AG
2022-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8113 |
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| author | Johan Lindqvist Justin Kolb Josine de Winter Paola Tonino Zaynab Hourani Siegfried Labeit Coen Ottenheijm Henk Granzier |
| author_facet | Johan Lindqvist Justin Kolb Josine de Winter Paola Tonino Zaynab Hourani Siegfried Labeit Coen Ottenheijm Henk Granzier |
| author_sort | Johan Lindqvist |
| collection | DOAJ |
| description | Nemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function. |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:36:25Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e917dcceb83247c8a4bc72402ff76c6a2023-11-30T22:23:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012315811310.3390/ijms23158113Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional BenefitsJohan Lindqvist0Justin Kolb1Josine de Winter2Paola Tonino3Zaynab Hourani4Siegfried Labeit5Coen Ottenheijm6Henk Granzier7Department of Cellular and Molecular Medicine, 1656 E Mabel Street, University of Arizona, Tucson, AZ 85724, USADepartment of Cellular and Molecular Medicine, 1656 E Mabel Street, University of Arizona, Tucson, AZ 85724, USADepartment of Physiology, Amsterdam UMC, Location VUMC, 1081 HV Amsterdam, The NetherlandsDepartment of Cellular and Molecular Medicine, 1656 E Mabel Street, University of Arizona, Tucson, AZ 85724, USADepartment of Cellular and Molecular Medicine, 1656 E Mabel Street, University of Arizona, Tucson, AZ 85724, USADepartment of Integrative Pathophysiology, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, GermanyDepartment of Cellular and Molecular Medicine, 1656 E Mabel Street, University of Arizona, Tucson, AZ 85724, USADepartment of Cellular and Molecular Medicine, 1656 E Mabel Street, University of Arizona, Tucson, AZ 85724, USANemaline myopathy (NM) is characterized by skeletal muscle weakness and atrophy. No curative treatments exist for this debilitating disease. NM is caused by mutations in proteins involved in thin-filament function, turnover, and maintenance. Mutations in nebulin, encoded by NEB, are the most common cause. Skeletal muscle atrophy is tightly linked to upregulation of MuRF1, an E3 ligase, that targets proteins for proteasome degradation. Here, we report a large increase in MuRF1 protein levels in both patients with nebulin-based NM, also named NEM2, and in mouse models of the disease. We hypothesized that knocking out MuRF1 in animal models of NM with muscle atrophy would ameliorate the muscle deficits. To test this, we crossed MuRF1 KO mice with two NEM2 mouse models, one with the typical form and the other with the severe form. The crosses were viable, and muscles were studied in mice at 3 months of life. Ultrastructural examination of gastrocnemius muscle lacking MuRF1 and with severe NM revealed a small increase in vacuoles, but no significant change in the myofibrillar fractional area. MuRF1 deficiency led to increased weights of various muscle types in the NM models. However, this increase in muscle size was not associated with increased in vivo or in vitro force production. We conclude that knocking out MuRF1 in NEM2 mice increases muscle size, but does not improve muscle function.https://www.mdpi.com/1422-0067/23/15/8113nemaline myopathynebulinmuscle atrophyMuRF1NEM2 and MAFbx |
| spellingShingle | Johan Lindqvist Justin Kolb Josine de Winter Paola Tonino Zaynab Hourani Siegfried Labeit Coen Ottenheijm Henk Granzier Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits International Journal of Molecular Sciences nemaline myopathy nebulin muscle atrophy MuRF1 NEM2 and MAFbx |
| title | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits |
| title_full | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits |
| title_fullStr | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits |
| title_full_unstemmed | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits |
| title_short | Removal of MuRF1 Increases Muscle Mass in Nemaline Myopathy Models, but Does Not Provide Functional Benefits |
| title_sort | removal of murf1 increases muscle mass in nemaline myopathy models but does not provide functional benefits |
| topic | nemaline myopathy nebulin muscle atrophy MuRF1 NEM2 and MAFbx |
| url | https://www.mdpi.com/1422-0067/23/15/8113 |
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