AUTHOR=Palzkill Victoria R. , Thome Trace , Murillo Ania L. , Khattri Ram B. , Ryan Terence E. 

TITLE=Increasing plasma L-kynurenine impairs mitochondrial oxidative phosphorylation prior to the development of atrophy in murine skeletal muscle: A pilot study

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.992413

DOI=10.3389/fphys.2022.992413

ISSN=1664-042X

ABSTRACT=<p><bold>Introduction:</bold> L-Kynurenine (L-Kyn), a product of tryptophan (Trp) catabolism, has been linked with impairments in walking speed, muscle strength/size, and physical function. The purpose of this pilot study was to develop a dietary model that elevates plasma L-Kyn levels in mice and characterize its impact on muscle health and function.</p><p><bold>Methods:</bold> Four-month-old C57BL6J male mice were randomized to either a L-Kyn supplemented (150 mg/kg) or chow diet for 10 weeks. Plasma L-Kyn and Trp levels were measured via mass spectrometry. Primary outcomes included assessments of muscle weights, myofiber cross-sectional area (CSA), nerve-stimulated contractile performance, and mitochondrial oxidative phosphorylation (OXPHOS) and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) production. Additional experiments in cultured myotubes explored the impact of enhancing L-Kyn metabolism.</p><p><bold>Results:</bold> Mice randomized to the L-Kyn diet displayed significant increases in plasma L-Kyn levels (<italic>p</italic> = 0.0028) and the L-Kyn/Trp ratio (<italic>p</italic> = 0.011) when compared to chow fed mice. Food intake and body weights were not different between groups. There were no detectable differences in muscle weights, myofiber CSA, or contractile performance. L-Kyn fed mice displayed reductions in mitochondrial OXPHOS (<italic>p</italic> = 0.05) and maximal ADP-stimulated respiration (<italic>p</italic> = 0.0498). In cultured myotubes, overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha prevented atrophy and proteolysis, as well as deficits in mitochondrial respiration with L-Kyn treatment.</p><p><bold>Conclusion:</bold> Dietary feeding of L-Kyn increases plasma L-Kyn levels and the L-Kyn/Trp ratio in healthy male mice. Mitochondrial impairments in muscle were observed in mice with elevated L-Kyn without changes in muscle size or function. Enhancing L-Kyn metabolism can protect against these effects in culture myotubes.</p>