1. Figure 1 Signalling pathways involved in muscle wasting in heart failure
Figure 1 | Signalling pathways involved in muscle wasting in heart failure. Pathways in muscle wasting that are associated with an anabolic–catabolic imbalance in heart failure. a | Anabolic pathways are activated by ghrelin and testosterone. Testosterone binds to cytoplasmic androgen receptors (AR) and stimulates protein synthesis via mitogen-activated protein kinases (MAPK). Ghrelin induces release of growth hormone (GH), which induces secretion of insulin-like growth factor 1 (IGF1). IGF1 binds to the IGF1 receptor (IGF1R) and the insulin receptor (IR), promoting phosphorylation of insulin receptor substrate 1 (IRS1). IRS1 activates the phosphoinositide 3-kinase–serine/threonine-protein kinase–mammalian target of rapamycin (PI3K–AKT–mTOR) signalling pathway, which stimulates protein synthesis, and inhibits glycogen synthase kinase 3 (GSK3). Several E3 ubiquitin-protein ligases block IRS1 signalling, such as elongin B and elongin C, CBL-B, F-box only protein 40 (FBXO40), and tripartite motif-containing protein 72 (TRIM72), which also targets the IR. The E3 ubiquitin-protein ligase TRIP12 induces degradation of the transcription factor SOX6, leading to a switch in the expression from MYH7 (specific to slow muscle fibres) to MYH4 (specific to fast muscle fibres). b | Catabolic pathways activate three main protein degradation systems: the ubiquitin–proteasome system (UPS) throught stimulation of FBXO32 (also known as MAFBX) and TRIM63 (also known as MURF1) expression; the autophagy–lysosome system (which degrades monoubiquinated proteins) mediated by forkhead box protein O (FOXO) transcription factors; and apoptosis, initiated by caspases. Binding of myostatin to the activin receptor type 2B (ACTRIIB) leads to activation of mothers against decapentaplegic homolog (SMAD) 2 and SMAD3, which in turn leads to inhibition of protein synthesis and induction of protein degradation via the UPS. Pro-inflammatory cytokines, mainly tumour necrosis factor (TNF), interleukin (IL)-1β, and IL-6, promote the generation of reactive oxygen species (ROS), and induce activation of nuclear factor (NF)-κB and FOXO proteins, which promote the expression of FBXO32 and TRIM63. FOXO is also activated by glucocorticoids via cytoplasmic glucocorticoid receptors (GR) and by angiotensin II via type 1 angiotensin II receptors (AT1). The dashed lines indicate an indirect action. Adapted from von Haehling, S. et al. Muscle wasting in heart failure: an overview. Int. J. Biochem. Cell Biol. 45, 2257–2265 (2013), with permission from Elsevier.
Adapted from von Haehling, S. et al. Muscle wasting in heart failure:
an overview. Int. J. Biochem. Cell Biol. 45, 2257–2265 (2013), with permission from Elsevier
von Haehling, S. et al. (2017) Muscle wasting and cachexia in heart failure: mechanisms and therapies
Nat. Rev. Cardiol. doi: /nrcardio