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Inhibition of IkappaB kinase alpha (IKKα) or IKKbeta (IKKβ) plus forkhead box O (Foxo) abolishes skeletal muscle
S A Reed1, S M Senf, E W Cornwell
1Department of Physical Therapy, University of Florida, 101 S. Newell Drive, Gainesville, FL 32610, USA.
Abstract:
Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor κB (NF-κB) and forkhead box O (Foxo). There is clear evidence that both NF-κB and Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-κB activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKKα and IKKβ), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKKα-EGFP, d.n. IKKβ-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKKα-EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization-induced fiber atrophy. Similarly, co-expression of d.n. IKKβ-EGFP and d.n. Foxo-DsRed inhibited the immobilization-induced fiber atrophy by 95%. These findings demonstrate that the combined effects of inhibiting immobilization-induced NF-κB and Foxo transcriptional activity has an additive effect on preventing immobilization-induced atrophy, indicating that NF-κB and Foxo have a cumulative effect on atrophy signaling and/or atrophy gene expression.
Insights
Inhibiting nuclear factor κB (NF-κB) and forkhead box O (Foxo) transcription factors together significantly prevents muscle atrophy caused by immobilization. Combined inhibition shows additive effects, highlighting their cumulative role in muscle wasting.
Area of Science:
- Muscle physiology and molecular biology
- Skeletal muscle atrophy mechanisms
- Transcription factor regulation
Background:
- Nuclear factor κB (NF-κB) and forkhead box O (Foxo) are key transcription factors activated during skeletal muscle wasting.
- Both NF-κB and Foxo are individually sufficient to cause muscle fiber atrophy and are required for significant atrophy during muscle disuse.
- The combined effect of inhibiting both NF-κB and Foxo during physiological muscle atrophy has not been previously investigated.
Purpose of the Study:
- To determine if combined inhibition of Foxo and NF-κB activation prevents muscle atrophy induced by cast immobilization.
- To investigate the additive or synergistic effects of inhibiting these two transcription factor families.
- To elucidate the roles of NF-κB and Foxo in the signaling pathways leading to immobilization-induced muscle atrophy.
Main Methods:
- Utilized a mouse model of cast immobilization for 7 days to induce muscle atrophy.
- Transfected immobilized muscles with dominant-negative (d.n.) expression plasmids for IKKα, IKKβ (inhibitors of NF-κB), and Foxo.
- Measured mean fiber cross-sectional area (CSA) in 72 muscles to quantify atrophy and inhibition effects.
Main Results:
- Immobilization caused a 47% decrease in fiber CSA in control muscles.
- Individual inhibition of IKKα, IKKβ, or Foxo reduced atrophy by 22%, 57%, and 76%, respectively.
- Combined inhibition of IKKα and Foxo reduced atrophy by 89%; combined inhibition of IKKβ and Foxo reduced atrophy by 95%.
Conclusions:
- Combined inhibition of NF-κB and Foxo transcriptional activity additively prevents immobilization-induced muscle atrophy.
- These findings demonstrate a cumulative effect of NF-κB and Foxo in muscle atrophy signaling and/or gene expression.
- Targeting both NF-κB and Foxo pathways offers a potential therapeutic strategy for mitigating muscle wasting conditions.
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