NOD2 activation induces oxidative stress contributing to mitochondrial dysfunction and insulin resistance in skeletal
Chandan K Maurya1, Deepti Arha1, Amit K Rai1
1Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Abstract:
Nucleotide-binding oligomerization domain protein-2 (NOD2) activation in skeletal muscle cells has been associated with insulin resistance, but the underlying mechanisms are not yet clear. Here we demonstrate the implication of oxidative stress in the development of mitochondrial dysfunction and insulin resistance in response to NOD2 activation in skeletal muscle cells. Treatment with the selective NOD2 ligand muramyl dipeptide (MDP) increased mitochondrial reactive oxygen species (ROS) generation in L6 myotubes. MDP-induced ROS production was associated with increased levels of protein carbonyls and reduction in citrate synthase activity, cellular ATP level, and mitochondrial membrane potential, as well as altered expression of genes involved in mitochondrial function and metabolism. Antioxidant treatment attenuated MDP-induced ROS production and restored mitochondrial functions. In addition, the presence of antioxidant prevented NOD2-mediated activation of MAPK kinases and the inflammatory response. This was associated with reduced serine phosphorylation of insulin receptor substrate-1 (IRS-1) and improved insulin-stimulated tyrosine phosphorylation of IRS-1 and downstream activation of Akt phosphorylation. These data indicate that oxidative stress plays a role in NOD2 activation-induced inflammatory response and that MDP-induced oxidative stress correlates with impairment of mitochondrial functions and induction of insulin resistance in skeletal muscle cells.
Insights
Nucleotide-binding oligomerization domain protein-2 (NOD2) activation causes oxidative stress and mitochondrial dysfunction in skeletal muscle, leading to insulin resistance. Antioxidants can reverse these effects, highlighting a key mechanism in metabolic health.
Area of Science:
- Cell Biology
- Metabolic Research
- Immunology
Background:
- Nucleotide-binding oligomerization domain protein-2 (NOD2) activation in skeletal muscle is linked to insulin resistance.
- The precise molecular mechanisms underlying this association remain largely unelucidated.
Purpose of the Study:
- To investigate the role of oxidative stress in NOD2 activation-induced mitochondrial dysfunction and insulin resistance in skeletal muscle cells.
- To explore the therapeutic potential of antioxidants in mitigating these effects.
Main Methods:
- L6 myotubes were treated with the NOD2 ligand muramyl dipeptide (MDP).
- Mitochondrial reactive oxygen species (ROS) generation, protein carbonyl levels, citrate synthase activity, ATP levels, and mitochondrial membrane potential were assessed.
- Gene expression related to mitochondrial function and metabolism was analyzed.
- The impact of antioxidant treatment on NOD2-mediated signaling pathways, including MAPK kinases, insulin receptor substrate-1 (IRS-1) phosphorylation, and Akt phosphorylation, was evaluated.
Main Results:
- MDP treatment significantly increased mitochondrial ROS production in L6 myotubes.
- This ROS increase correlated with elevated protein carbonyls, reduced citrate synthase activity, lower ATP levels, and diminished mitochondrial membrane potential.
- Antioxidant intervention successfully attenuated MDP-induced ROS, restored mitochondrial function, and prevented NOD2-mediated inflammatory responses.
- Antioxidants also inhibited NOD2-induced MAPK activation and improved insulin signaling by reducing IRS-1 serine phosphorylation and enhancing insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt.
Conclusions:
- Oxidative stress is a critical mediator in NOD2 activation-induced inflammation and insulin resistance within skeletal muscle cells.
- MDP-induced oxidative stress impairs mitochondrial function, contributing to the development of insulin resistance.
- Antioxidant strategies show promise in counteracting NOD2-mediated detrimental effects on skeletal muscle metabolism and insulin sensitivity.
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