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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

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 1

Comparison of NF-κB activation in Ikk2f/f and Ikk2mko muscles.

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Comparison of NF-κB activation in Ikk2f/f and Ikk2mko muscles.
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(A) Deletion of the floxed alleles only in Ikk2mko skeletal muscles as shown by Southern blot analysis on genomic DNA isolated from different tissues. (B) Decreased expression of IKK2 in different Ikk2mko muscles, shown by immunoblotting of total muscle extracts. The other subunits, IKK1 and NEMO, remain intact. (C) Unchanged levels of IKK proteins in other tissues. H, heart; G, gastrocnemius; T, TA; D, diaphragm; S, soleus; B, brain; K, kidney; Sp, spleen; C, control from brain-specific IKK2 deletion. (D) IP in 300 μg of whole-muscle extracts from Ikk2f/f and Ikk2mko mice was performed with a polyclonal antibody against NEMO, followed by Western blot (WB) analysis with a monoclonal antibody against IKK1 or IKK2 as indicated. MEF, mouse embryonic fibroblasts. (E) Nuclear translocation of NF-κB was demonstrated by EMSA. (F) Evaluation of IKK activity. Total protein (300 μg) from normal or challenged (injured or denervated) muscles was IP with a NEMO antibody and subjected to a kinase assay using a truncated glutathione S-transferase–IκBa (aa residues 1–54) protein as substrate. DN, denervated; NDN, nondenervated.

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

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