Figure 4. Dulaglutide attenuates inflammation and downregulates the expression of OPA-1-TLR-9 signaling in aged mice. (A) Protein levels of OPA-1 and TLR-9 in TA muscle (B) mRNA expression of IL-6 and TNF-α in TA muscle (C) mRNA expression of Opa-1, TLR-9, IL-6, and TNF-α in QD muscle. (D) Schematic diagram of the proposed mechanism of action of dulaglutide in muscle tissue. Our data suggest that dulaglutide mediated-GLP-1 receptor signaling may regulate muscle atrophy in aged mice via the following three independent and interconnected signaling pathways: 1) Dulaglutide stimulates PGC-1α, which in turn enhances mitochondrial biogenesis and function, subsequently suppressing endosomal TLR9 mediated NF-kB signaling cascades in muscle. This signaling involves an increase in proinflammatory cytokines and muscle atrophic factors expression. 2) The increase in proinflammatory cytokines activates myostatin signaling cascades and 3) NF-kB signaling cascades thereby inducing proinflammatory cytokines and muscle atrophic factors expression. In contrast, dulaglutide treatment suppresses these signaling pathways by regulating cAMP-PKA-NF-kB and AKT-FoxO. All values are expressed as the mean ± SE. Significant differences are indicated as ***p < 0.001, **p < 0.01, or *p < 0.05 compared to young mice + vehicle or aged mice + vehicle. N = 5–8/group.