1. The role of ZEB1 in mediating the protective effects of metformin on skeletal muscle atrophy.
- Author
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Jia P, Che J, Xie X, Han Q, Ma Y, Guo Y, and Zheng Y
- Subjects
- Animals, Mice, Male, MyoD Protein metabolism, MyoD Protein genetics, Interleukin-1beta metabolism, Mice, Inbred C57BL, Disease Models, Animal, Myoblasts, Skeletal metabolism, Myoblasts, Skeletal drug effects, Myoblasts, Skeletal pathology, Lipopolysaccharides, Myogenin metabolism, Myogenin genetics, Cell Line, Metformin pharmacology, Zinc Finger E-box-Binding Homeobox 1 metabolism, Zinc Finger E-box-Binding Homeobox 1 genetics, Muscular Atrophy prevention & control, Muscular Atrophy drug therapy, Muscular Atrophy metabolism, Muscular Atrophy etiology, Muscle, Skeletal metabolism, Muscle, Skeletal drug effects, Muscle, Skeletal pathology, Cell Differentiation drug effects, Hypoglycemic Agents pharmacology
- Abstract
Metformin is an important antidiabetic drug that has the potential to reduce skeletal muscle atrophy and promote the differentiation of muscle cells. However, the exact molecular mechanism underlying these functions remains unclear. Previous studies revealed that the transcription factor zinc finger E-box-binding homeobox 1 (ZEB1), which participates in tumor progression, inhibits muscle atrophy. Therefore, we hypothesized that the protective effect of metformin might be related to ZEB1. We investigated the positive effect of metformin on IL-1β-induced skeletal muscle atrophy by regulating ZEB1 in vitro and in vivo. Compared with the normal cell differentiation group, the metformin-treated group presented increased myotube diameters and reduced expression levels of atrophy-marker proteins. Moreover, muscle cell differentiation was hindered, when we artificially interfered with ZEB1 expression in mouse skeletal myoblast (C2C12) cells via ZEB1-specific small interfering RNA (si-ZEB1). In response to inflammatory stimulation, metformin treatment increased the expression levels of ZEB1 and three differentiation proteins, MHC, MyoD, and myogenin, whereas si-ZEB1 partially counteracted these effects. Moreover, marked atrophy was induced in a mouse model via the administration of lipopolysaccharide (LPS) to the skeletal muscles of the lower limbs. Over a 4-week period of intragastric administration, metformin treatment ameliorated muscle atrophy and increased the expression levels of ZEB1. Metformin treatment partially alleviated muscle atrophy and stimulated differentiation. Overall, our findings may provide a better understanding of the mechanism underlying the effects of metformin treatment on skeletal muscle atrophy and suggest the potential of metformin as a therapeutic drug., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)
- Published
- 2024
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