Fig. 1

Signaling pathways involved in muscle wasting. During muscle atrophy, there is a lack of binding of insulin like growth factor 1 (IGF-1)/insulin to their receptors. IGF-1 activates IRS–PI3K–Akt–mTORC1 signaling. mTOR complex blocks proteolysis by inhibiting autophagy initiation factors Unc-51 like autophagy activating kinase (ULK) 1/2. In atrophy response there is also an inhibition of Akt protein by blocking its phosphorylation which results in inhibition of Myod and Myogenin-important myogenic regulatory proteins that are expressed during myogenesis. Thus, inhibition of Akt can activate the forkhead box O family of transcription factors (FoxO) members that translocate to the nucleus and promote gene transcription of MAFbx and MurF-1, responsible for proteasome activity and ubiquitination. TNF alpha signaling perturbations may also cause atrophy by downregulate NF-kB-a transcription factor NF-kB activation whose is required for maximal atrophy; NF-kB activation induces transcriptional upregulation of the E3 ubiquitin-ligase MuRF1 and MAFbx. Myostatin and its signaling pathway are involved in myogenesis and atrophy. The myostatin dimer first binds to ActRIIB, then to ALK4/5 to form a complex with Smad2/3/4. Different transcription factors bind to the Smad2/3/4 complex, resulting in various functions of the Smad signaling pathway. These pathways mediate the transcription of myogenic regulatory factors (myogenin, Myf5, MyoD), MuRF-1, and atrogin-1 to regulate myogenic differentiation and muscle mass. Abbreviations: TNF-a: Tumor necrosis factor alpha; IGF-1: insulin-like growth factor 1; GDF-11: Growth differentiation factor 11; ALK2/3: Activin receptor-like kinase 2 and 3; MAPK: Mitogen Activated Protein Kinase; PI3K: phosphatidylinositol 3-kinase; AKT: Protein kinase B; FoxO: forkhead box transcription factor; p65: protein 65; MAFbx: muscle atrophy F-box; MuRF-1: Muscle RING Finger-1; mTOR: mammalian target of rapamycin; NF-kB: nuclear factor kappa B; LC3II: Microtubule-associated protein 1A/1B-light chain 3 II; IKK: IkappaB kinase; TRADD: Tumor necrosis factor receptor type 1-associated DEATH domain