UCHL1 regulates Interleukin‐6 expression in skeletal muscles

Abstract

Chronic low grade inflammation is a hallmark of aging and has been linked to aging related dysfunction and disease. As the largest tissue mass, skeletal muscles express and release several inflammatory cytokines including interleukin‐6 (IL‐6). With altered function and metabolism, aged muscles can be a major source of inflammatory cytokine in aging. Ubiquitin C‐terminal Hydrolase L1 (UCHL1) was originally found in the brain. Our recent study revealed that UCHL1 is inducible and upregulated in skeletal muscles in mice by denervation and lipopolysaccharide (LPS). In differentiated C2C12 cells. UCHL1 gene knockdown using siRNA significantly increased Interleukin 6 (IL‐6) level in the media. Consistent with this in vitro data, the plasma level of IL‐6 was also higher in mice with global or muscle specific UCHL1 gene knockout. Moreover, UCHL1 gene knockdown in C2C12 significantly reduced the protein level of IκB, a key inhibitory molecule for the activation of NF‐kB signaling pathway. Reduced protein level of IκB was also observed in muscles from UCHL1 knockout mice. These data suggest a potential novel mechanism by which UCHL1 controls IL‐6 expression in skeletal muscle by stabilizing IκB and thus inhibiting activation of NF‐kB pathway. Given the impaired UCHL1 function in the brain with aging, it is plausible to hypothesize that aging may also reduce the UCHL1 control of NF‐kB activation in skeletal muscle, leading to muscle‐derived chronic inflammation in aging.Support or Funding InformationThis study is supported by NIH grant 1R15HL118696 and 1R03AG051926, the USD BBS graduate program, USD CBBRe pilot grant, and USD PQCD pilot grant.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.