Journal article
GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle
JCI insight, Vol.8(22), e171772
11/22/2023
DOI: 10.1172/jci.insight.171772
PMCID: PMC10721312
PMID: 37815864
Abstract
Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of Growth Arrest and DNA Damage Inducible Alpha (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MEKK4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
Details
- Title: Subtitle
- GADD45A is a mediator of mitochondrial loss, atrophy, and weakness in skeletal muscle
- Creators
- Hawley E KunzZachary C RyanMatthew D StrubPatrick M VanderboomCarrie J HeppelmannSarah ChauZachary D Von RuffSean P KilroeAndrew T McKeenJason M DierdorffJennifer I SternKarl A NathChad E GrueterVitor A LiraAndrew R JudgeBlake B RasmussenK Sreekumaran NairIan R LanzaGeorge R MarcotteScott M EbertMatthew J MillerChristopher M Adams
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.8(22), e171772
- DOI
- 10.1172/jci.insight.171772
- PMID
- 37815864
- PMCID
- PMC10721312
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: R01AR071762; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01AG060637; DOI: 10.13039/100000002, name: National Institutes of Health, award: R44AG047684; DOI: 10.13039/100000002, name: National Institutes of Health, award: R44AR069400; DOI: 10.13039/100000738, name: US Department of Veterans Affairs, award: I01BX00976; DOI: 10.13039/100000968, name: American Heart Association, award: 23PRE1019231; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01AG054454; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01AG064386; DOI: 10.13039/100000002, name: National Institutes of Health, award: P30AG071150; DOI: 10.13039/100000002, name: National Institutes of Health, award: UL1TR001439; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01DK133401
- Language
- English
- Electronic publication date
- 10/10/2023
- Date published
- 11/22/2023
- Academic Unit
- Cardiovascular Medicine; Orthopedics and Rehabilitation; Craniofacial Anomalies Research Center; Dental Research; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984475075302771
Metrics
32 Record Views