1. Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes.
- Author
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Bernacchioni C, Ghini V, Squecco R, Idrizaj E, Garella R, Puliti E, Cencetti F, Bruni P, and Donati C
- Subjects
- Animals, Cell Differentiation, Cell Line, Gene Expression Regulation, Humans, Metabolomics methods, Mice, Models, Biological, Muscle Fibers, Skeletal metabolism, Muscle Fibers, Skeletal pathology, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscular Atrophy genetics, Muscular Atrophy metabolism, Muscular Atrophy pathology, Myoblasts metabolism, Myoblasts pathology, Patch-Clamp Techniques, Phosphorylation drug effects, Phosphotransferases (Alcohol Group Acceptor) metabolism, Signal Transduction, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors metabolism, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha metabolism, Lysophospholipids metabolism, Muscle Fibers, Skeletal drug effects, Phosphotransferases (Alcohol Group Acceptor) genetics, Sphingosine analogs & derivatives, Sphingosine-1-Phosphate Receptors genetics, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) plays an important role in skeletal muscle biology. S1P, generated by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK1/2), exerts most of its actions through its specific receptors, S1P
1-5 . Here, we provide experimental evidence that TNFα induces atrophy and autophagy in skeletal muscle C2C12 myotubes, modulating the expression of specific markers and both active and passive membrane electrophysiological properties. NMR-metabolomics provided a clear picture of the deep remodelling of skeletal muscle fibre metabolism induced by TNFα challenge. The cytokine is responsible for the modulation of S1P signalling axis, upregulating mRNA levels of S1P2 and S1P3 and downregulating those of SK2. TNFα increases the phosphorylated form of SK1, readout of its activation. Interestingly, pharmacological inhibition of SK1 and specific antagonism of S1P3 prevented the increase in autophagy markers and the changes in the electrophysiological properties of C2C12 myotubes without affecting metabolic remodelling induced by the cytokine, highlighting the involvement of S1P signalling axis on TNFα-induced atrophy in skeletal muscle.- Published
- 2021
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