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Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration
Foteini Mourkioti, … , Manolis Pasparakis, Nadia Rosenthal
Foteini Mourkioti, … , Manolis Pasparakis, Nadia Rosenthal
Published November 1, 2006
Citation Information: J Clin Invest. 2006;116(11):2945-2954. https://doi.org/10.1172/JCI28721.
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Research Article Genetics Article has an altmetric score of 4

Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration

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Abstract

NF-κB is a major pleiotropic transcription factor modulating immune, inflammatory, cell survival, and proliferative responses, yet the relevance of NF-κB signaling in muscle physiology and disease is less well documented. Here we show that muscle-restricted NF-κB inhibition in mice, through targeted deletion of the activating kinase inhibitor of NF-κB kinase 2 (IKK2), shifted muscle fiber distribution and improved muscle force. In response to denervation, IKK2 depletion protected against atrophy, maintaining fiber type, size, and strength, increasing protein synthesis, and decreasing protein degradation. IKK2-depleted mice with a muscle-specific transgene expressing a local Igf-1 isoform (mIgf-1) showed enhanced protection against muscle atrophy. In response to muscle damage, IKK2 depletion facilitated skeletal muscle regeneration through enhanced satellite cell activation and reduced fibrosis. Our results establish IKK2/NF-κB signaling as an important modulator of muscle homeostasis and suggest a combined role for IKK inhibitors and growth factors in the therapy of muscle diseases.

Authors

Foteini Mourkioti, Paschalis Kratsios, Tom Luedde, Yao-Hua Song, Patrick Delafontaine, Raffaella Adami, Valeria Parente, Roberto Bottinelli, Manolis Pasparakis, Nadia Rosenthal

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Figure 7

Combined IGF-1 supplementation and IKK2 inhibition enhances protection against muscle atrophy.

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Combined IGF-1 supplementation and IKK2 inhibition enhances protection a...
(A) Comparison of gastrocnemius weights from control (black line), Ikk2mko (dashed line), mIgf-1 (light blue line), and mIgf-1/Ikk2f/f (dark blue line) mice at 7, 14, and 28 days after denervation. Values represent denervated muscle weights after normalization to sham-operated muscle weight (n = 5 mice per time point). (B–I) Enhanced maintenance of muscle-fiber size in gastrocnemius muscle from mIgf-1 and mIgf-1/Ikk2f/f denervated muscle. Magnification, ×100 (B–E); ×200 (F–I). (J) Sustenance in the gastrocnemius fiber CSA in Ikk2mko, mIgf-1, and mIgf-1/Ikk2f/f atrophied muscle. (K) MuRF1 and (L) atrogin-1/MAFbx mRNA levels in gastrocnemius muscles of control (n = 4), Ikk2mko (n = 4), mIgf-1 (n = 3), and mIgf-1/Ikk2f/f (n = 4) muscles as determined by quantitative real-time RT-PCR. Denervated values were normalized to nondenervated values. **Mean values differ significantly from those of control (P < 0.002).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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