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Heart failure (HF) is the end stage of cardiovascular disease and is characterized by the loss of myocytes caused by cell death. Puerarin has been found to improve HF clinically, and animal study findings have confirmed its anti-cell-death properties. However, the underlying mechanisms remain unclear, especially with respect to the impact on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death in HF. Here, ferroptosis-like cell death was observed in erastin- or isoprenaline (ISO)-treated H9c2 myocytes in vitro and in rats with aortic banding inducing HF, characterized by reduced cell viability with increased lipid peroxidation and labile iron pool. Interestingly, the increased iron overload and lipid peroxidation observed in either rats with HF or H9c2 cells incubated with ISO were significantly blocked by puerarin administration. These results provide compelling evidence that puerarin plays a role in inhibiting myocyte loss during HF, partly through ferroptosis mitigation, suggesting a new mechanism of puerarin as a potential therapy for HF. more...

Background Severe peripheral nerve injury leads to skeletal muscle atrophy and impaired limb function that is not sufficiently improved by existing treatments. Fibroblast growth factor 6 (FGF6) is involved in tissue regeneration and is dysregulated in denervated rat muscles. However, the way that FGF6 affects skeletal muscle repair after peripheral nerve injury has not been fully elucidated. Methods In this study, we investigated the role of FGF6 in the regeneration of denervated muscles using myoblast cells and an in vivo model of peripheral nerve injury. Results FGF6 promoted the viability and migration of C2C12 and primary myoblasts in a dose-dependent manner through FGFR1-mediated upregulation of cyclin D1. Low concentrations of FGF6 promoted myoblast differentiation through FGFR4-mediated activation of ERK1/2, which upregulated expression of MyHC, MyoD, and myogenin. FGFR-1, FGFR4, MyoD, and myogenin were not upregulated when FGF6 expression was inhibited in myoblasts by shRNA-mediated knockdown. Injection of FGF6 into denervated rat muscles enhanced the MyHC-IIb muscle fiber phenotype and prevented muscular atrophy. Conclusion These findings indicate that FGF6 reduces skeletal muscle atrophy by relying on the ERK1/2 mechanism and enhances the conversion of slow muscle to fast muscle fibers, thereby promoting functional recovery of regenerated skeletal muscle after innervation. more...

Loss of myocytes caused by cell death plays a key role during heart failure (HF). Activated autophagy and increased ferroptosis have been observed in HF and proved to promote its progression. However, the underlying mechanisms remain unclear. Here, results from integrated bioinformatical analysis showed TLR4 and NADPH oxidase 4 (NOX4) were included in up-regulated differentially expressed genes (DEGs), and had an interaction between each other inferred by the DEGs-associated protein-protein interaction (PPI) network. To explore the role of TLR4-NOX4 in autophagy and ferroptosis, knock-down of TLR4 and NOX4 through lentiviral delivery of siRNA to the myocardium were applied respectively in HF rats induced by aortic banding, and the indicators of autophagy and ferroptosis were detected. Results revealed that either TLR4 or NOX4 knock-down significantly improved left ventricular remodeling and reduced myocytes death. Simultaneously, activated autophagy and ferroptosis in rats with HF were remarkably retarded by either TLR4 and NOX4 knock-down, suggesting TLR4-NOX4 as a potential therapeutic target for HF through inhibiting autophagy- and ferroptosis-mediated cell death. more...