RESUMO
The antioxidant capability of herbal remedies has attracted widespread attention, but their molecular mechanisms in a muscle atrophy model have not been explored. The aim of the present study was to compare the bioactivity of sucrose challenged mice following treatment with ATG125. Here, through a combination of transcriptomic and biomedical analysis, herbal formula ATG125, a phytochemicalrich formula, was identified as a protective factor against muscle atrophy in sucrose challenged mice. Gene ontology (GO) identified differentially expressed genes that were primarily enriched in the 'negative regulation of proteolysis', 'cellular amino acid metabolic process', 'lipoprotein particle' and 'cell cycle', all of which were associated with the ATG125mediated prevention of muscle atrophy, particularly with regard to mitochondrial biogenesis. In skeletal muscle, a set of mitochondrialrelated genes, including angiopoietinlike 4, nicotinamide riboside kinase 2 (Nmrk2), pyruvate dehydrogenase lipoamide kinase isozyme 4, Asctype amino acid transporter 1 and mitochondrial uncoupling protein 3 (Ucp3) were markedly upregulated following ATG125 intervention. An increase in Nmrk2 and Ucp3 expression were noted after ATG125 treatment, in parallel with upregulation of the 'nicotinate and nicotinamide metabolism' pathway, as determined using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Furthermore, KEGG pathway analysis revealed the downregulation of 'complement and coagulation cascades', 'cholesterol metabolism', 'biosynthesis of amino acids' and 'PPAR signaling pathway', which were associated with the downregulation of serine (or cysteine) peptidase inhibitor clade A member (Serpina)3, Serpina1b, Serpina1d, Serpina1e, apolipoprotein (Apo)a1 and Apoa2, all of which were cardiovascular and diabetesassociated risk factors and were regulated by ATG125. In addition, ATG125 treatment resulted in downregulated mRNA expression levels of ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2, troponinI1, troponinC1 and troponinT1 in young adult gastrocnemius muscle compared with the sucrose group. Nuclear factorκBhypoxia inducible factor1αTGFß receptor typeIIvascular endothelial growth factor staining indicated that ATG125 decreased sucroseinduced chronic inflammation. ATG125 was sufficient to prevent muscle atrophy, and this protective effect may be mediated through upregulation of AKT phosphorylation, upregulating the insulin growth factor1Rinsulin receptor substratePI3KAKT pathway, which in turn resulted in a forkhead box Odependent decrease in protein degradation pathways, including regulation of atrogin1 and E3 ubiquitinprotein ligase TRIM63. Peroxisomeproliferator activated receptor γ coactivator 1α (PGC1α) was decreased in young adult mice challenged with sucrose. ATG125 treatment significantly increased PGC1α and significantly increased UCP1,2,3 expression levels, which suggested ATG125 poised the mitochondria for uncoupling of respiration. This effect is consistent with the increased SIRT1 levels and may explain an increase in mitochondria biogenesis. Taken together, the present study showed that ATG125, as an integrator of protein synthesis and degradative pathways, prevented muscle wasting.