Sunday, May 11, 2025
5/11/2025
Determining the Biological Effects of Mitochondrial Acyl Toxicity - PROJECT SUMMARY During acute metabolic stress and chronic metabolic disease, such as obesity and diabetes, the accumulation of fatty acid oxidation intermediary metabolites has long been suspected of toxicity. Among these possible lipotoxic metabolites are long-chain acylcarnitines (LCACs), which purportedly interfere with critical physiological processes including insulin signaling, calcium homeostasis, and mitochondrial function. However, mechanistically linking defects in these processes to LCAC accumulation has been difficult due to a lack of LCAC-accumulating pre-clinical models. We overcame this barrier by developing a unique mouse model of LCAC accumulation by deleting the enzyme that catabolizes LCACs, carnitine palmitoyltransferase-2 specifically in skeletal muscle (Cpt2Sk-/-). Consistent with the suspected roles of LCACs effects on biology, our preliminary data demonstrate that Cpt2Sk-/- muscles have reduced force production and mitochondrial dysfunction. Our preliminary data also demonstrate large accumulation of LCACs within oxidative muscle fibers, thus are the most vulnerable to potential LCAC toxicity. While our Cpt2Sk-/- model provides consistently elevated LCACs, the physiological outcomes are confounded by energy deprivation due to mitochondrial FAO deficiency. To mitigate concerns surrounding this confounding variable, we will employ three complimentary mouse models of muscle- specific FAO deficiency: 1) Cpt2Sk-/- that accumulate LCACs across the cell; 2) carnitine acylcarnitine translocase (CactSk-/-) mice that accumulate LCACs outside of the mitochondria; and 3) acyl-CoA synthetase 1 (Acsl1Sk-/-) mice that do not accumulate LCACs at all. Here, we will use this three-model system to determine the role of LCACs on insulin signaling, calcium homeostasis, and mitochondrial function. Results will be the first to provide requisite experimental contrast to unveil direct versus indirect effects of LCACs on cell physiology.
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