Phytochemical-rich herbal formula ATG-125 protects against sucrose-induced gastrocnemius muscle atrophy by rescuing Akt signaling and improving mitochondrial dysfunction in young adult mice

The antioxidant capability of herbal remedies has attractedwidespreadattention,buttheirmolecularmechanisms 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 aTG-125. Here, through a combination of transcriptomic and biomedical analysis, herbal formula aTG-125, a phytochemical-rich 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’,allofwhichwereassociatedwiththeaTG-125-mediated prevention of muscle atrophy, particularly with regard to mitochondrial biogenesis. in skeletal muscle, a set of mitochondrial-related genes, including angiopoietin-like 4, nicotinamide riboside kinase 2 (Nmrk2), pyruvate dehydrogenase lipoamide kinase isozyme 4, asc-type amino acid transporter 1 and mitochondrial uncoupling protein 3 (Ucp3) were markedly upregulated following aTG-125 intervention. an increase in Nmrk2 and Ucp3 expression were noted after aTG-125 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 diabetes-associated risk factors and were regulated by aTG-125. in addition, aTG-125 treatment resulted in downregulated mrna expression levels of aTPase sarcoplasmic/endoplasmic reticulum ca²⁺ transporting 2, troponin-I1, troponin-C1 and troponin-T1 in young adult gastrocnemius muscle compared with the sucrose group. nuclear factor-κB-hypoxia inducible factor-1α-TGFβ receptor type-ii-vascular endothelial growth factor staining indicated that aTG-125 decreased sucrose-induced chronic inflammation. aTG-125 was sufficient to prevent muscle atrophy, and this protective effect may be mediated through upregulation of aKT phosphorylation, upregulating the insulin growth factor-1r-insulin receptor substrate-Pi3K-aKT pathway, which in turn resulted in a forkhead box o-dependent decrease in protein degradation pathways, including regulation of atrogin1 and e3 ubiquitin-protein ligase TriM63. Peroxisome-proliferator activated receptor γ coactivator 1α (PGc1α) was decreased in young adult mice challenged with sucrose. ATG-125 treatment significantly increased PGC1α and significantly increased UCP-1,2,3 expression levels, which suggested aTG-125 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 aTG-125, as an integrator of protein synthesis and degradative pathways, prevented muscle wasting.