Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection

Abstract

MafBx and Murf are two new rat E3 ubiquitin ligases induced in muscle atrophy. Our goal was to investigate whether lipopolysaccharide (LPS) injection, a model of muscle catabolism, is associated with increased expression of MafBx and Murf. LPS (750 W Wg/100 g body weight) induces MafBx and Murf mRNA (respectively, 23-fold and 33-fold after 12 h; P 6 0.001). A transient induction of tumor necrosis factor-K K mRNA (21-fold; P 6 0.001 at 3 h) and a decrease of insulin like growth factor-I mRNA (50%; P 6 0.001 at 6 h), two potential regulators of the ubiquitin^proteasome system were also demonstrated. In summary, MafBx and Murf mRNA are upregulated in response to LPS and might play a role in the muscle proteolysis observed. ß

Key signalling factors and pathways in the molecular determination of skeletal muscle phenotype

“…Thus, atrophy is as much an active degradation process as a passive one from reduced stimulation of the anabolic (hyperplastic and hypertrophic) pathways. Of the different protein degradation pathways (Costelli et al, 2003), the ATPdependent ubiquitin-proteasome proteolytic system is thought to be of major importance in skeletal muscle (Dehoux et al, 2003;Glass, 2003a). In this process, ubiquitin (Ub) is activated by an ubiquitin-activating enzyme (E1 family) and conjugated to a substrate protein by ubiquitin-conjugating enzyme (E2 family) in conjunction with ubiquitin protein ligase (E3 ligase family).…”

“…During muscle atrophy, many of the genes encoding the Ub-proteasome pathway are upregulated , including E2 (such as E2 14K and UbcH2) and E3 (such as E3a / UBr1) genes (Li et al, 2003;Lecker et al, 2004). In particular, two E3 ubiquitin ligases, MuRF1 (muscle ring finger 1) and MAFbx (muscle atrophy F-box or atrogin-1) have been identified as mediators of muscle atrophy (Bodine et al, 2001a;Dehoux et al, 2003). MuRF1 and MAFbx are selectively induced in skeletal muscle and heart when subjected to a variety of atrophic conditions, such as denervation and glucocorticoid treatment.…”

“…Their absence in null knock-out mice led to the preservation of muscle mass under atrophying conditions (Bodine et al, 2001a). TNF-a stimulated proteolysis may be mediated through the increased expression of MAFbx and MuRF1 (Dehoux et al, 2003;Glass 2005). MuRF1 contains three domains: a RING-finger domain, required for ubiquitin ligase activity, a B-box of unclear function, and a coil-coil domain, which may be required for heterodimerisation with a related protein MuRF2.…”

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

“…During muscle atrophy, including that induced by fasting [19][20][21][22], the expression of MuRF-1 and MAFbx have been reported to be increased. MuRF-1 ubiquitinates myofibrillar and cytoskeleton proteins and metabolic enzymes in preparation for their subsequent breakdown in the proteasome [57][58][59][60].…”

“…Elevated levels of interleukin 6 (IL-6) may also reduce food intake [17] and contribute to muscle wasting via abolishing the normally anabolic effect of insulin-like growth factor 1 (IGF-1) [18]. The muscle breakdown may be realised by an increased expression of the muscle specific ubiquitin ligases, MAFbx and MuRF-1, that play an important role in protein breakdown, as observed during undernutrition [19][20][21][22] and systemic inflammation [23]. It is thus possible that undernutrition and inflammation may induce the expression of the muscle specific E3 ubiquitin ligases and thereby contribute to the loss of body and muscle mass during alfacalcidol supplementation.…”