Genetic Inhibition of Chac1 Leads to Dysregulation of Body Composition

Abstract

CHAC1 is a gamma‐glutamylcyclotransferase downstream of ATF4 in the Unfolded Protein Response. CHAC1 degrades glutathione, the primary, intracellular antioxidant, and decreases Notch signaling. Notch is the receptor for a well‐conserved signaling pathway that is essential for development and proper maintenance of adult tissues, such as mucle and bone. Due to the importance of glutathione and Notch, it is likely that CHAC1 is critical for cell function and development. Chac1−/− mice were generated to elucidate the effects of Chac1 in vivo; however, knockout of Chac1 is lethal. Interestingly, Chac1+/− mice have decreased body weight, suggesting Chac1 is important in body composition regulation.To dissect the underlying cause for reduced body mass in Chac1+/− mice, four metrics were analyzed: food intake, fat mass, muscle mass, and bone function. Analysis of food intake illustrates that there is no change in food intake; thus, food intake does not account for the decrease in body weight, but does suggest a misregulation of energy balance. Abdominal fat pad weight is not consistently changed at any 6, 13, or 33 weeks of age ages, suggesting no changes in fat mass. Chac1+/− mice of both sexes have decreased gastrocnemius weights at 6 weeks and 33 weeks of age, suggesting decreased muscle mass as the cause of the reduced body weight. Finally, markers of osteoblasts were analyzed in the femur of male and female Chac1+/− mice versus control. Markers for osteoblasts, such as Runx2 and Col1a1, are decreased in Chac1+/− mice at 6 weeks. These data suggest that there is a decrease in osteoblast differentiation and decreased bone density.Overall, these data illustrate that genetic inhibition of Chac1 in mice leads to multiple changes in body composition, including lower muscle mass and changes in bone development, demonstrating the importance of Chac1 in the proper regulation of muscle and bone. Furthermore, Chac1 may play an important role in the progression of muscle and bone pathology in conditions such as osteoporosis, aging, and muscle wasting.Support or Funding InformationNIH #HL09470; COBRE P30GM106392; Louisiana Board of Regents Fellowship #LESQSF(2012‐17)‐GF‐08 to RRC

Ferroptosis Contributed Genes in the Soleus Muscle After Endurance Training in Older Rats

“…Current results showed that regular exercise could signi cantly reduce "CHAC1" mRNA expression. It is an enzyme that could be upregulated in response to ER stress through "PERK/elF2α/ATF4/CHOP" signaling, Nrf2, ATF3 and P53 pathways [17]. CHAC1 is an enzyme that degrades GSH, which is an important antioxidant molecule.…”

“…Crawford et al (2018) stated that genetic inhibition of CHAC1 in mice leads to numerous Modi cations in body con guration, including decreased amount of muscle tissue and changes in bone growth, which shows the importance of CHAC1 in muscles and bones proper regulation. In addition, CHAC1 could be a crucial factor in the development of muscle and bone pathology in conditions such as osteoporosis, aging, and muscle wasting [17]. Glutamate-cysteine ligase (GCL) as the rst rate-limiting enzyme of GSH biosynthesis is considered as well.…”

CHAC1 promotes cell ferroptosis and enhances radiation sensitivity in thyroid carcinoma

“…CHAC1 has a structure (BtrG/γ-GCT fold) and an active site similar to γ-GCT and mediates the degradation of cellular glutathione [12]. Knockout of the CHAC1 gene resulted in embryonic lethality, suggesting that CHAC1 is an important intracellular functional regulator [13]. Overexpression of CHAC1 led to intracellular glutathione depletion and increased ROS levels, and decreased GPX4 protein levels [14].…”