Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance

Abstract

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.

Regulation of Skeletal Muscle Atrophy in Cachexia by MicroRNAs and Long Non-coding RNAs

“…Skeletal muscle, which can contract or stretch, is vital for body metabolism, homeostasis, and movement (Agudelo et al, 2019;Amoasii et al, 2019;Fiorenza et al, 2019). The development of skeletal muscle has been studied in depth, and a variety of regulatory molecules and complex mechanisms are involved in skeletal muscle development.…”

Physical Exercise as Kynurenine Pathway Modulator in Chronic Diseases: Implications for Immune and Energy Homeostasis

“…Therefore, regular aerobic exercise could be proposed to enhance these adaptations. 60 In summary, evidence with and without directly investigating exercise indicates the extended involvement of the KYN pathway in the maintenance or even improvement of energy metabolism (Figure 2) through differing mechanisms and tissue types. A potential overarching explanation could be of evolutionary nature.…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…[109][110][111] It will be important to study whether non-coding RNAs are also an important part of the muscle physiological metabolism regulation network. [109][110][111] It will be important to study whether non-coding RNAs are also an important part of the muscle physiological metabolism regulation network.…”

“…Skeletal muscle is a tissue that plays a crucial role in body metabolism, homeostasis movement. [109][110][111] It will be important to study whether non-coding RNAs are also an important part of the muscle physiological metabolism regulation network. Future work on the molecular mechanisms of lncRNAs and circRNAs in skeletal muscle development and diseases will lead to an integrated understanding of skeletal muscle biology.…”