@article{a7b527c7174b4b67965459758cf0dbcd,
title = "Sustained NFκB inhibition improves insulin sensitivity but is detrimental to muscle health",
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",
author = "Ning Zhang and Valentine, {Joseph M.} and You Zhou and Li, {Mengyao E.} and Yiqiang Zhang and Arunabh Bhattacharya and Walsh, {Michael E.} and Fischer, {Katherine E.} and Austad, {Steven N.} and Pawel Osmulski and Maria Gaczynska and Shoelson, {Steven E.} and {Van Remmen}, Holly and Chen, {Hung I.} and Yidong Chen and Hanyu Liang and Nicolas Musi",
note = "Funding Information: This work was supported by grants from the NIH (R01-DK80157 and R01-DK089229), and the American Diabetes Association to N.M. A.B. was supported by an award from the NIH (K01AG038555) and an award from the American Federation for Aging Research. J.V. and M.E.W. were supported by a Biology of Aging T32 Training Grant (T32 AG021890), and Y.C. was supported by NCI Cancer Center Shared Resources NCI P30CA54174 and NIH CTSA 1UL1RR025767-01. This research also was supported by the San Antonio Nathan Shock Center of Excellence on Aging Biology (P30 AG013319), by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (MUSC) (P30 CA138313) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE, Department of Biochemistry, MUSC (P20 RR017677). RNA-seq experiment was performed by the Genome Sequencing Facility of the Greehey Children's Cancer Research Institute, UTHSCSA. We thank Drs. Sophie Hussey, Sangeeta Ghosh, Miranda Orr, Rochelle Buffenstein, and Kelly Grimes for their helpful insights. Also, we thank Dr. Ji Li and Ms. Vanessa Soto for excellent technical support and Dr. Jonathan Gelfond for biostatistical input. Publisher Copyright: {\textcopyright} 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",
year = "2017",
month = aug,
doi = "10.1111/acel.12613",
language = "English (US)",
volume = "16",
pages = "847--858",
journal = "Aging cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "4",
}