Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle

Area of Science:

• Toxicology
• Cell Biology
• Biochemistry

Background:

• Developing robust in vitro models is crucial for early detection of xenobiotic-induced skeletal muscle toxicity.
• Novel sulfonyl isoxazoline herbicides have been linked to skeletal muscle adverse effects in vivo.
• Transcriptomics data from in vivo studies revealed pathways related to mitochondrial dysfunction and oxidative stress.

Purpose of the Study:

• To validate the use of an in vitro rat skeletal muscle (L6) model for predicting in vivo xenobiotic toxicity.
• To investigate the mechanisms of skeletal muscle toxicity induced by sulfonyl isoxazoline herbicides.
• To assess the utility of L6 cell models in capturing mitochondrial dysfunction and oxidative stress.

Main Methods:

• Utilized an in vitro rat skeletal muscle (L6) model.
• Applied transcriptomics data from in vivo rat studies.
• Investigated mitochondrial dysfunction, oxidative stress, and apoptosis using L6 metabolic models.
• Exposed L6 cells to sulfonyl isoxazoline compounds in galactose media.

Main Results:

• In vitro L6 models confirmed that sulfonyl isoxazoline compounds induce mitochondrial dysfunction, mitochondrial superoxide production, and apoptosis.
• The in vitro findings aligned with transcriptomics data from in vivo studies.
• The L6 galactose media model demonstrated sensitivity to mitochondrial perturbations relevant to skeletal muscle toxicity.

Conclusions:

• The L6 skeletal muscle model effectively identifies in vivo mechanisms of xenobiotic-induced toxicity.
• This in vitro model can be used for early screening and potency ranking of novel xenobiotics.
• The L6 galactose media model shows promise for studying mitochondrial dysfunction in skeletal muscle toxicology.