TRB3 regulates skeletal muscle mass in food deprivation–induced atrophy

Abstract

Tribbles 3 (TRB3) is a pseudokinase that has been found in multiple tissues in response to various stress stimuli, such as nutrient deprivation and endoplasmic reticulum (ER) stress. We recently found that TRB3 has the potential to regulate skeletal muscle mass at the basal state. However, it has not yet been explored whether TRB3 regulates skeletal muscle mass under atrophic conditions. Here, we report that food deprivation for 48 h in mice significantly reduces muscle mass by ∼15% and increases TRB3 expression, which is associated with increased ER stress. Interestingly, inhibition of ER stress in C2C12 myotubes reduces food deprivation–induced expression of TRB3 and muscle‐specific E3‐ubiquitin ligases. In further in vivo experiments, muscle‐specific TRB3 transgenic mice increase food deprivation–induced muscle atrophy compared with wild‐type (WT) littermates presumably by the increased proteolysis. On the other hand, TRB3 knockout mice ameliorate food deprivation–induced atrophy compared with WT littermates by preserving a higher protein synthesis rate. These results indicate that TRB3 plays a pivotal role in skeletal muscle mass regulation under food deprivation–induced muscle atrophy and TRB3 could be a pharmaceutical target to prevent skeletal muscle atrophy.—Choi, R. H., McConahay, A., Silvestre, J. G., Moriscot, A. S., Carson, J. A., Koh, H.‐J. TRB3 regulates skeletal muscle mass in food deprivation–induced atrophy. FASEB J. 33, 5654–5666 (2019). http://www.fasebj.org

Reduced rDNA transcription diminishes skeletal muscle ribosomal capacity and protein synthesis in cancer cachexia

“…43 To stimulate ribophagy and muscle wasting, myotubes were maintained in differentiation medium (DM), incubated with tumor conditioned media (CM) from confluent ES-2 culture plates, or switched to PBS to promote nutrient deprivation-induced autophagy and myotube atrophy. 44,45 Autophagy was blocked by incubating myotubes with Chloroquine diphosphate salt (CLQ) (MP Biomedicals, Santa Ana, CA) in DMSO at 25 µM concentration for 24 hours before replacing the media with CLQ in DM (DM + CLQ) or PBS (PBS + CLQ) for an additional 1 hour and 6 hours In separate experiments, we inhibited ubiquitin-mediated proteolysis by treating myotubes with the reversible proteasome inhibitor Carbobenzoxy-Leu-Leu-Leucinal (MG-132) at 25 µM alone, or in combination with CLQ for 6 hours without CLQ pretreatment.…”

An improvement in skeletal muscle mitochondrial capacity with short‐term aerobic training is associated with changes in Tribbles 1 expression

“…Knockdown of TRIB3 in skeletal muscle improved insulin sensitivity in a rat model for insulin resistance (Weismann et al, 2011); however, rats exposed to short-term exercise training improved glucose tolerance without changes in skeletal muscle TRIB3 protein (Canciglieri et al, 2018). TRIB3 has also been implicated in the regulation of muscle mass, as well as exercise capacity (An et al, 2014;Choi et al, 2019); however, RNA-sequencing data we have collected from human vastus lateralis muscle demonstrates that TRIB1 is the predominant form expressed in human muscle with minimal expression of TRIB3 (data not shown). Therefore, these observations indicate that alterations in TRIB1 expression may be involved in the adaptation to exercise in human skeletal muscle.…”

Animal models of sarcopenia

“…It has been demonstrated that TRB3 caused muscle fiber atrophy and a decrease in muscle function by negatively modulating protein turnover in the condition of food deprivation (Choi et al, 2017(Choi et al, , 2019 and could inhibit the myogenic differentiation of C2C12 (mouse myoblast) cells (Kato & Du, 2007). Shang et al acquired TRB3 knockout mice and found that sarcopenia was attenuated in these mice compared with aged controls via the alleviation of atrophy and fibrosis of skeletal muscles (Shang et al, 2020 As noted below, in C. elegans (Depuydt et al, 2013;Duhon & Johnson, 1995;Herndon et al, 2002) and in Drosophila (Demontis & Perrimon, 2010;Owusu-Ansah, Song, & Perrimon, 2013), genetic reduction in the insulin/IGF1 signaling pathway, which causes increased nuclear translocation of DAF-16 (FOXO in mammals), results in lifespan extension and reduced sarcopenia in these organisms.…”

“…TRB3 was previously reported to exhibit an age‐related increase in expression (Meyer, Schenk, & Lieber, 2013) and play a vital role in cell proliferation, differentiation, and fibrosis. It has been demonstrated that TRB3 caused muscle fiber atrophy and a decrease in muscle function by negatively modulating protein turnover in the condition of food deprivation (Choi et al, 2017, 2019) and could inhibit the myogenic differentiation of C2C12 (mouse myoblast) cells (Kato & Du, 2007). Shang et al acquired TRB3 knockout mice and found that sarcopenia was attenuated in these mice compared with aged controls via the alleviation of atrophy and fibrosis of skeletal muscles (Shang et al, 2020).…”