Aging Cell: Sustained NFκB inhibition improves insulin sensitivity but is detrimental to muscle health

Ning Zhang 1Joseph M Valentine 1You Zhou 1Mengyao E Li 1 2Yiqiang Zhang 1Arunabh Bhattacharya 1Michael E Walsh 1Katherine E Fischer 1Steven N Austad 1Pawel Osmulski 1Maria Gaczynska 1Steven E Shoelson 2Holly Van Remmen 1Hung I Chen 3 4Yidong Chen 3 4Hanyu Liang 1Nicolas Musi 1 5

Abstract

Older adults universally suffer from sarcopenia and approximately 60-70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging-related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFκB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases (e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFκB pathway would protect against aging-related sarcopenia and insulin resistance. Aged mice with muscle-specific overexpression of a super-repressor IκBα mutant (MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild-type mice. In MISR mice, NFκB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy (e.g., myostatin). We conclude that the mechanism behind aging-induced sarcopenia is NFκB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFκB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function.

Keywords: NFκB; aging; insulin resistance; sarcopenia; skeletal muscle.

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