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

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), a 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 that NRF2 activation improves muscle force production during ambulatory conditions but is not sufficient to prevent muscle atrophy or weakness following 7 days of HU.