GLP-2 ameliorates D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a signaling pathway in C2C12 cells and mice.

BACKGROUND: The study aimed to investigate the effect of Glucagon-like peptide-2 (GLP-2) on muscle aging in vivo and in vitro. METHODS: Six-week-old C57BL/6J mice were administered with D-galactose (200 mg/kg/day, intraperitoneally) for 8weeks, followed by daily subcutaneous injections of GLP-2 (300 or 600 µg/kg/day) for 4weeks. Skeletal muscle function and mass were evaluated using relative grip strength and muscle weight. The sizes and types of muscle fibers and apoptosis were assessed through histological analysis, immunofluorescence staining, and TUNEL staining, respectively. C2C12 myotubes were treated with D-galactose (40 mg/mL) and GLP-2. Protein expression of differentiation-related myogenic differentiation factor D (MyoD), myogenin (MyoG), and myosin heavy chain (Myhc), degradation-related Muscle RING finger 1 (MuRF-1), and muscle atrophy F-box (MAFbx)/Atrogin-1, and apoptosis-related B-cell leukemia/lymphoma 2 (Bcl-2) and Bax, were assessed using western blots. The Pi3k inhibitor LY294002 was applied to investigate whether GLP-2 regulated myogenesis and myotube aging via IGF-1/Pi3k/Akt/FoxO3a signaling pathway. RESULTS: The results demonstrated that GLP-2 significantly reversed the decline in muscles weight, relative grip strength, diameter, and cross-sectional area of muscle fibers induced by D-galactose in mice. Apart from suppressing the expressions of MuRF-1 and Atrogin-1 in the muscles and C2C12 myotubes, GLP-2 significantly increased the expressions of MyoD, MyoG, and Myhc compared to the D-galactose. GLP-2 significantly suppressed cell apoptosis. Western blot analysis indicated that the regulation of GLP-2 may be attributed to the activation of theIGF-1/Pi3k/Akt/FoxO3a phosphorylation pathway. CONCLUSIONS: This study suggested that GLP-2 ameliorated D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a pathway.

Unraveling the molecular crosstalk and immune landscape between COVID-19 infections and ischemic heart failure comorbidity: New insights into diagnostic biomarkers and therapeutic approaches.

BACKGROUND: Coronavirus disease 2019 (COVID-19), resulting from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), remains a persistent global health concern. Evidence has highlighted a significant association between COVID-19 and ischemic heart failure (IHF), contributing to disease progression and increased mortality. This study identified diagnostic biomarkers for these comorbidities and elucidated disease progression's molecular mechanisms. METHODS: We retrieved differentially expressed gene (DEG) data for COVID-19 and IHF from publicly available microarray and RNA-Seq datasets to investigate the underlying mechanisms and potential pathways associated with the co-occurrence of COVID-19 and IHF. By intersecting the results from the two diseases, we obtained diagnostic biomarkers using SVM-RFE and LASSO algorithms. Animal experiments and immunological analyses were conducted to help understand the association between SARS-CoV-2 and IHF in patients, enabling early diagnosis of disease progression. Finally, we analyzed the regulatory network of critical genes and identified potential drug compounds that could target the genetic links identified in our study. RESULTS: 1974 common DEGs were identified between COVID-19 and IHF, contributing to disease progression and potential cancer risk by participating in immune and cancer-related pathways. In addition, we identified six hub genes (VDAC3, EIF2AK2, CHMP5, FTL, VPS4A, and CHMP4B) associated with the co-morbidity, and their diagnostic potential was confirmed through validation using relevant datasets and a mouse model. Functional enrichment analysis and examination of immune cell infiltration revealed immune dysregulation after disease progression. The comorbid hub genes exhibited outstanding immunomodulatory capacities. We also constructed regulatory networks tightly linked to both disorders, including transcription factors (TFs), miRNAs, and genes at both transcriptional and post-transcriptional levels. Finally, we identified 92 potential drug candidates to enhance the precision of anti-comorbidity treatment strategies. CONCLUSION: Our study reveals a shared pathogenesis between COVID-19 and IHF, demonstrating that their coexistence exacerbates disease severity. By identifying and consolidating hub genes as pivotal diagnostic biomarkers for COVID-19 and IHF comorbidity, we have made significant advancements in understanding the underlying mechanisms of these conditions. Moreover, our study highlights dysregulated immunity and increased cancer risk in the advanced stages of disease progression. These findings offer novel perspectives for diagnosing and treating IHF progression during SARS-CoV-2 infection.