Journal article
Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
Redox biology, Vol.48, pp.102196-102196
12/2021
DOI: 10.1016/j.redox.2021.102196
PMCID: PMC8646998
PMID: 34872044
Abstract
Mutations in the human LMNA gene cause a collection of diseases called laminopathies, which includes muscular dystrophy and dilated cardiomyopathy. The LMNA gene encodes lamins, filamentous proteins that form a meshwork on the inner side of the nuclear envelope. How mutant lamins cause muscle disease is not well understood, and treatment options are currently limited. To understand the pathological functions of mutant lamins so that therapies can be developed, we generated new Drosophila models and human iPS cell-derived cardiomyocytes. In the Drosophila models, muscle-specific expression of the mutant lamins caused nuclear envelope defects, cytoplasmic protein aggregation, activation of the Nrf2/Keap1 redox pathway, and reductive stress. These defects reduced larval motility and caused death at the pupal stage. Patient-derived cardiomyocytes expressing mutant lamins showed nuclear envelope deformations. The Drosophila models allowed for genetic and pharmacological manipulations at the organismal level. Genetic interventions to increase autophagy, decrease Nrf2/Keap1 signaling, or lower reducing equivalents partially suppressed the lethality caused by mutant lamins. Moreover, treatment of flies with pamoic acid, a compound that inhibits the NADPH-producing malic enzyme, partially suppressed lethality. Taken together, these studies have identified multiple new factors as potential therapeutic targets for LMNA-associated muscular dystrophy.
•Drosophila models of LMNA muscular dystrophy exhibited redox imbalance.•Amino acid substitutions in all three domains of lamins caused reductive stress.•iPS cell-derived cardiomyocytes showed an altered response to NAC treatment.•Genetic manipulation of autophagy regulators suppressed lethality caused by mutant lamins.•Pamoic acid, a malic enzyme inhibitor, suppressed lethality caused by mutant lamins.
Details
- Title: Subtitle
- Modulation of muscle redox and protein aggregation rescues lethality caused by mutant lamins
- Creators
- Gary S. Coombs - Biology Department, Waldorf University, Forest City, IA, USAJose L. Rios-Monterrosa - University of IowaShuping Lai - Medical College of WisconsinQiang Dai - Medical College of WisconsinAshley C. Goll - University of IowaMargaret R. Ketterer - University of IowaMaria F. Valdes - Waldorf CollegeNnamdi Uche - Medical College of WisconsinIvor J. Benjamin - Medical College of WisconsinLori L. Wallrath - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Redox biology, Vol.48, pp.102196-102196
- DOI
- 10.1016/j.redox.2021.102196
- PMID
- 34872044
- PMCID
- PMC8646998
- NLM abbreviation
- Redox Biol
- ISSN
- 2213-2317
- eISSN
- 2213-2317
- Publisher
- Elsevier B.V
- Grant note
- DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases; DOI: 10.13039/100005202, name: Muscular Dystrophy Association
- Language
- English
- Date published
- 12/2021
- Academic Unit
- Microbiology and Immunology; Biochemistry and Molecular Biology; University College Courses
- Record Identifier
- 9984288721602771
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