NFκB is a transcription factor that controls immune and inflammatory processes. In muscle, NFκB has been implicated in regulation of muscle mass/function, metabolism, and mitochondrial function. Yet, NFκB’s role in aging-related changes to skeletal muscle and heart remains less defined. To investigate the role of NFκB in aging skeletal muscle and heart, we study a mouse model (MISR mice) with suppressed NFκB signaling in these tissues. Recently we found that these mice have exacerbated loss of skeletal muscle mass during aging. Here, we report that NFκB suppression caused reductions in skeletal muscle mass as early as 1 month of age. Aging per se (in WT mice) lead to a global downregulation of mitochondrial function (reduced respiration and enhanced reactive oxygen species production) and expression of mitochondrial biogenesis genes in skeletal muscle. Furthermore, suppression of NFκB signaling in skeletal muscle resulted in mitochondrial function defects in early life (4 months old), whereas in aged mice (30-33 months old) it had the opposite effect. Contrary to findings in skeletal muscle, in the heart aging increased mitochondrial respiration and reactive oxygen species production (in WT mice) and NFκB suppression protected against the aging related changes to reactive oxygen species production. We conclude that suppression of the canonical NFκB pathway has antagonistic pleiotropic effects (detrimental in early life and advantageous in aging animals) on mitochondrial function in skeletal muscle, but is beneficial throughout the lifespan in the heart. Furthermore, canonical NFκB signaling regulates muscle development and cellular metabolism at the transcriptional and functional levels.
J. Valentine: None. M.E. Li: None. N. Zhang: None. S.E. Shoelson: Consultant; Self; Par Pharmaceuticals. Stock/Shareholder; Self; Catabasis Pharmaceuticals. N. Musi: None.