Muscle-specific Keap1 deletion enhances force production but does not prevent inactivity-induced muscle atrophy in mice

Miranda, E. R.; Shahtout, J. L.; Watanabe, S.; Milam, N.; Karasawa, T.; Rout, S.; Atkinson, D. L.; Holland, W. L.; Drummond, M. J.; Funai, K.

doi:10.1101/2024.10.03.616570

bioRxiv · 10.1101/2024.10.03.616570

Muscle-specific Keap1 deletion enhances force production but does not prevent inactivity-induced muscle atrophy in mice

Miranda, E. R.·Shahtout, J. L.·Watanabe, S.·Milam, N.·Karasawa, T.·Rout, S.·Atkinson, D. L.·Holland, W. L.·Drummond, M. J.·Funai, K.

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Abstract

Immobilization-associated muscle atrophy and weakness appear to be driven in part by oxidative stress. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) is a critical redox rheostat that regulates oxidative stress responses, and its deletion is known to accelerate muscle atrophy and weakness during aging (sarcopenia) or denervation. Conversely, pharmacologic activation of NRF2 extends mouse lifespan and attenuates sarcopenia. Similarly, deletion of Kelch-like ECH-associated Protein 1 (Keap1), negative regulator of NRF2, enhances exercise capacity. The purpose of this study was to determine whether muscle-specific Keap1 deletion is sufficient to prevent muscle atrophy and weakness in mice following 7-days of hindlimb unloading (HU). To test this hypothesis, control (Ctrl) and tamoxifen inducible, muscle-specific Keap1 knockout (mKO) mice were subjected to either normal housing (Sham) or HU for 7 days. Activation of NRF2 in muscle was confirmed by increased mRNA of NRF2 targets thioredoxin 1 (Txn1) and NAD(P)H quinone dehydrogenase 1 (NQO1) in mKO mice. Keap1 deletion had an effect to increase force-generating capacity at baseline. However, muscle masses, cross sectional area, and ex vivo force were not different between mKO and Ctrl HU mice. In addition, muscle 4-hydroxynonenal-modified proteins and protein carbonyls were unaffected by Keap1 deletion. These data suggest NRF2 activation improves muscle force production during ambulatory conditions but is not sufficient prevent muscle atrophy or weakness following 7-days of HU. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/616570v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@433d1eorg.highwire.dtl.DTLVardef@61996dorg.highwire.dtl.DTLVardef@19fe734org.highwire.dtl.DTLVardef@104205f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Miranda, E. R., Shahtout, J. L., Watanabe, S., Milam, N., Karasawa, T., Rout, S., Atkinson, D. L., Holland, W. L., Drummond, M. J., Funai, K.. 2024-10-04. Muscle-specific Keap1 deletion enhances force production but does not prevent inactivity-induced muscle atrophy in mice. https://doi.org/10.1101/2024.10.03.616570

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