TGF-β requires the activation of canonical and non-canonical signalling pathways to induce skeletal muscle atrophy

Abstract

The transforming growth factor type-beta (TGF-β) induces skeletal muscle atrophy characterised by a decrease in the fibre's diameter and levels of myosin heavy chain (MHC), also as an increase of MuRF-1 expression. In addition, TGF-β induces muscle atrophy by a mechanism dependent on reactive oxygen species (ROS). TGF-β signals by activating both canonical Smad-dependent, and non-canonical signalling pathways such as ERK1/2, JNK1/2, and p38 MAPKs. However, the participation of canonical and non-canonical signalling pathways in the TGF-β atrophic effect on skeletal muscle is unknown. We evaluate the impact of Smad and MAPK signalling pathways on the TGF-β-induced atrophic effect in C2C12 myotubes. The results indicate that TGF-β activates Smad2/3, ERK1/2 and JNK1/2, but not p38 in myotubes. The pharmacological inhibition of Smad3, ERK1/2 and JNK1/2 activation completely abolished the atrophic effect of TGF-β. Finally, the inhibition of these canonical and non-canonical pathways did not decrease the ROS increment, while the inhibition of ROS production entirely abolished the phosphorylation of Smad3, ERK1/2 and JNK1/2. These results suggest that TGF-β requires Smad3, ERK1/2 and JNK1/2 activation to produce skeletal muscle atrophy. Moreover, the induction of ROS by TGF-β is an upstream event to canonical and non-canonical pathways.

Age and multiparity related urethral sphincter muscle dysfunction in a rabbit model: Potential roles of TGF‐β and Wnt‐β catenin signaling pathways

“…Overall, our findings show age‐related loss of wall thickness as well as function, that is, decrease in the UCP and these observations are consistent with prior reports . Collectively, our studies demonstrate age related upregulation of two key (Wnt and TGF‐β) fibrogenic signaling and an important atrophy (MuRF‐1) pathways that is regulated by TGF‐β …”

“…Overall, our findings suggest that age‐related USM fibrosis is associated with upregulation of both Wnt and TGF‐β‐mediated signaling pathways. In addition to fibrosis, TGF‐β is known to regulate MuRF‐1, a well‐recognized marker of atrophy, and our observations support a role for this protein in USM atrophy …”

“…Wnt signaling pathway is also known to play an important role in injury‐related fibrosis in several organs such as lungs, liver, myocardium, kidney, and skin . Wnt signaling also regulates the expression of transforming growth factor (TGF‐β), a key fibrogenic agent and TGF‐β in turn regulates muscle atrophy by activation of MuRF‐1 (Muscle RING‐finger protein‐1) expression . The exact role of MuRF‐1 in EUS muscle atrophy is not well understood and as such warrants investigation.…”

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

“…Also, there was no difference between the protein expression of TGF‐β isoforms and tumour stage (Supporting Information, Figure S3). Moreover, TGF‐β signalling can be activated both by canonical SMAD‐dependent pathway and by non‐canonical signalling pathways, such as ERK1/2, JNK1/2, and p38 MAPKs . Proteins of the canonical TGF‐β pathway (SMAD2 and SMAD3 activation) showed no differences between the groups ( Figure B; P = 0.628 and P = 0.400, respectively).…”

“…Proteins of the canonical TGF‐β pathway (SMAD2 and SMAD3 activation) showed no differences between the groups ( Figure B; P = 0.628 and P = 0.400, respectively). In addition to provoking activation of SMAD, TGF‐β also modulates the activity of MAPK pathway, an important signalling pathway that plays a central role in the activation of muscle catabolism in animal models of CC . The protein expression of factors related to MAPK pathway was altered in the tumour of cachectic patients in relation to WSC: p38, JNK, and MEK1 were increased ( P = 0.025, P = 0.050, and P = 0.024, respectively), while MSK1 protein expression did not show alterations between the groups ( Figure C).…”