Late-onset megaconial myopathy in mice lacking group I Paks
Abstract Background Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myobla...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-02-01
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| Series: | Skeletal Muscle |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13395-019-0191-4 |
| _version_ | 1819225692659777536 |
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| author | Giselle A. Joseph Margaret Hung Aviva J. Goel Mingi Hong Marysia-Kolbe Rieder Noam D. Beckmann Madhavika N. Serasinghe Jerry E. Chipuk Parvathi M. Devarakonda David J. Goldhamer Paulina Aldana-Hernandez Jonathan Curtis René L. Jacobs Robert S. Krauss |
| author_facet | Giselle A. Joseph Margaret Hung Aviva J. Goel Mingi Hong Marysia-Kolbe Rieder Noam D. Beckmann Madhavika N. Serasinghe Jerry E. Chipuk Parvathi M. Devarakonda David J. Goldhamer Paulina Aldana-Hernandez Jonathan Curtis René L. Jacobs Robert S. Krauss |
| author_sort | Giselle A. Joseph |
| collection | DOAJ |
| description | Abstract Background Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during postnatal development and regeneration in mice. However, the roles of Pak1 and Pak2 in adult muscle homeostasis are unknown. Choline kinase β (Chk β) is important for adult muscle homeostasis, as autosomal recessive mutations in CHKβ are associated with two human muscle diseases, megaconial congenital muscular dystrophy and proximal myopathy with focal depletion of mitochondria. Methods We analyzed mice conditionally lacking Pak1 and Pak2 in the skeletal muscle lineage (double knockout (dKO) mice) over 1 year of age. Muscle integrity in dKO mice was assessed with histological stains, immunofluorescence, electron microscopy, and western blotting. Assays for mitochondrial respiratory complex function were performed, as was mass spectrometric quantification of products of choline kinase. Mice and cultured myoblasts deficient for choline kinase β (Chk β) were analyzed for Pak1/2 phosphorylation. Results dKO mice developed an age-related myopathy. By 10 months of age, dKO mouse muscles displayed centrally-nucleated myofibers, fibrosis, and signs of degeneration. Disease severity occurred in a rostrocaudal gradient, hindlimbs more strongly affected than forelimbs. A distinctive feature of this myopathy was elongated and branched intermyofibrillar (megaconial) mitochondria, accompanied by focal mitochondrial depletion in the central region of the fiber. dKO muscles showed reduced mitochondrial respiratory complex I and II activity. These phenotypes resemble those of rmd mice, which lack Chkβ and are a model for human diseases associated with CHKβ deficiency. Pak1/2 and Chkβ activities were not interdependent in mouse skeletal muscle, suggesting a more complex relationship in regulation of mitochondria and muscle homeostasis. Conclusions Conditional loss of Pak1 and Pak2 in mice resulted in an age-dependent myopathy with similarity to mice and humans with CHKβ deficiency. Protein kinases are major regulators of most biological processes but few have been implicated in muscle maintenance or disease. Pak1/Pak2 dKO mice offer new insights into these processes. |
| first_indexed | 2024-12-23T10:13:38Z |
| format | Article |
| id | doaj.art-31317f8c00e84f5db79bb5fc800436e5 |
| institution | Directory Open Access Journal |
| issn | 2044-5040 |
| language | English |
| last_indexed | 2024-12-23T10:13:38Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Skeletal Muscle |
| spelling | doaj.art-31317f8c00e84f5db79bb5fc800436e52022-12-21T17:50:53ZengBMCSkeletal Muscle2044-50402019-02-019111710.1186/s13395-019-0191-4Late-onset megaconial myopathy in mice lacking group I PaksGiselle A. Joseph0Margaret Hung1Aviva J. Goel2Mingi Hong3Marysia-Kolbe Rieder4Noam D. Beckmann5Madhavika N. Serasinghe6Jerry E. Chipuk7Parvathi M. Devarakonda8David J. Goldhamer9Paulina Aldana-Hernandez10Jonathan Curtis11René L. Jacobs12Robert S. Krauss13Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiDepartment of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiDepartment of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiDepartment of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiDepartment of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiGraduate School of Biological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Oncological Sciences, Icahn School of Medicine at Mount SinaiDepartment of Molecular & Cell Biology, University of ConnecticutDepartment of Molecular & Cell Biology, University of ConnecticutDepartment of Agricultural, Food and Nutritional Science, University of AlbertaDepartment of Agricultural, Food and Nutritional Science, University of AlbertaDepartment of Agricultural, Food and Nutritional Science, University of AlbertaDepartment of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount SinaiAbstract Background Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during postnatal development and regeneration in mice. However, the roles of Pak1 and Pak2 in adult muscle homeostasis are unknown. Choline kinase β (Chk β) is important for adult muscle homeostasis, as autosomal recessive mutations in CHKβ are associated with two human muscle diseases, megaconial congenital muscular dystrophy and proximal myopathy with focal depletion of mitochondria. Methods We analyzed mice conditionally lacking Pak1 and Pak2 in the skeletal muscle lineage (double knockout (dKO) mice) over 1 year of age. Muscle integrity in dKO mice was assessed with histological stains, immunofluorescence, electron microscopy, and western blotting. Assays for mitochondrial respiratory complex function were performed, as was mass spectrometric quantification of products of choline kinase. Mice and cultured myoblasts deficient for choline kinase β (Chk β) were analyzed for Pak1/2 phosphorylation. Results dKO mice developed an age-related myopathy. By 10 months of age, dKO mouse muscles displayed centrally-nucleated myofibers, fibrosis, and signs of degeneration. Disease severity occurred in a rostrocaudal gradient, hindlimbs more strongly affected than forelimbs. A distinctive feature of this myopathy was elongated and branched intermyofibrillar (megaconial) mitochondria, accompanied by focal mitochondrial depletion in the central region of the fiber. dKO muscles showed reduced mitochondrial respiratory complex I and II activity. These phenotypes resemble those of rmd mice, which lack Chkβ and are a model for human diseases associated with CHKβ deficiency. Pak1/2 and Chkβ activities were not interdependent in mouse skeletal muscle, suggesting a more complex relationship in regulation of mitochondria and muscle homeostasis. Conclusions Conditional loss of Pak1 and Pak2 in mice resulted in an age-dependent myopathy with similarity to mice and humans with CHKβ deficiency. Protein kinases are major regulators of most biological processes but few have been implicated in muscle maintenance or disease. Pak1/Pak2 dKO mice offer new insights into these processes.http://link.springer.com/article/10.1186/s13395-019-0191-4Pak kinaseSkeletal muscleMyopathyMitochondriaCholine kinase |
| spellingShingle | Giselle A. Joseph Margaret Hung Aviva J. Goel Mingi Hong Marysia-Kolbe Rieder Noam D. Beckmann Madhavika N. Serasinghe Jerry E. Chipuk Parvathi M. Devarakonda David J. Goldhamer Paulina Aldana-Hernandez Jonathan Curtis René L. Jacobs Robert S. Krauss Late-onset megaconial myopathy in mice lacking group I Paks Skeletal Muscle Pak kinase Skeletal muscle Myopathy Mitochondria Choline kinase |
| title | Late-onset megaconial myopathy in mice lacking group I Paks |
| title_full | Late-onset megaconial myopathy in mice lacking group I Paks |
| title_fullStr | Late-onset megaconial myopathy in mice lacking group I Paks |
| title_full_unstemmed | Late-onset megaconial myopathy in mice lacking group I Paks |
| title_short | Late-onset megaconial myopathy in mice lacking group I Paks |
| title_sort | late onset megaconial myopathy in mice lacking group i paks |
| topic | Pak kinase Skeletal muscle Myopathy Mitochondria Choline kinase |
| url | http://link.springer.com/article/10.1186/s13395-019-0191-4 |
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