Figure 3.

| Interplay of signaling pathway and COPD biomarkers. Myostatin on binding to its receptor ActRIIB causes the phosphorylation of the Smad2 and Smad3, which further recruits Smad4 and forms a trio-complex which via gene transcription in the nucleus results in sarcopenia. On the other hand, myostatin binding also reduces the Akt activity, which usually keeps the FOXO in the cytosol by phosphorylating it under normal conditions. FOXO on dephosphorylation due to reduced Akt activity translocates into the nucleus and transcribes the genes involved in sarcopenia via proteolysis. Activated FOXO also reduces the expression of PGC-1α, which via atrophy leads to sarcopenia. ROS causes a reduction in the levels of SIRT1 and the endogenous antioxidant GSH. SIRT1 inhibits NF-kß signaling under normal conditions, but under stress conditions, it is unable to do so; thus, NF-kß translocates into the nucleus and starts its downstream effects, such as a reduction in the PGC-1α expression. SIRT1 under normal circumstances increases the PGC-1α expression, but under stress conditions, it cannot do so; thus, the expression of PGC-1α gets suppressed. ROS also increases the lysosomal SA-ß-gal, and tumor suppressors p16INK4A and p53 levels associated with cellular senescence, which further secrete SASP. ROS mediated inflammation is caused by reduction in the levels of HDAC2 under stress conditions via activated NF-kß. ROS also reduces the level of PI3K/Akt/mTOR pathway expression, typically involved in protein synthesis. However, under stress conditions, protein synthesis is reduced and causes the skeletal muscle protein desmin’s proteolysis, which is involved in muscle wasting via atrophy. Upper head arrows show increased expression, while lower head arrows represent the decreased expression. Different colored arrows are used to indicate the paths of different markers and their outcomes. N represents no significant change. ActRIIB, activin A receptor, type IIB; PI3K, phosphatidylinositol 3-kinase; Akt, serine/threonine protein kinase B; mTOR, mammalian target of rapamycin; NF-kß, nuclear factor kappa light chain enhancer of activated B cells; SASP, senescence associated secretory phenotype; HDAC2, histone deacetylase 2; HAT, histone acetyltransferase; p16INK4A, cyclin-dependent kinase inhibitor 2A; p53, 53 kDa tumor protein; PGC-1α, peroxisome proliferator-activated receptor c coactivator 1; SIRT1, sirtuin 1; Smad2, mothers against decapentaplegic homologue 2; FOXO, forkhead box protein O; GSH, glutathione.