# Elevating Circulating L‐Kynurenine Promotes Frailty in Aging Mice

## TL;DR

Elevated L-Kynurenine worsens age-related frailty in mice, but increased PGC1α in muscles helps protect against this decline.

## Contribution

This study shows that PGC1α overexpression in skeletal muscle mitigates L-Kyn-induced frailty in aging mice.

## Key findings

- MCK-PGC1α transgenic mice showed significantly higher KAT expression compared to wildtype mice.
- L-Kyn diet increased frailty in wildtype mice, but this was mitigated by MCK-PGC1α overexpression.
- MCK-PGC1α mice had improved mitochondrial function regardless of L-Kyn diet.

## Abstract

L‐Kynurenine (L‐Kyn), a product of tryptophan catabolism, increases with age and has been associated with reduced physical function and increased frailty in humans. Robustly expressed in skeletal muscle, kynurenine aminotransferases (KATs) degrade L‐Kyn into kynurenic acid and are regulated by the transcriptional co‐regulator peroxisome proliferator–activated receptor gamma coactivator 1‐alpha (PGC1α).

The study investigated (1) if elevating L‐Kyn levels via a diet intervention exacerbates an age‐related decline in physical, muscle and mitochondrial functions and (2) if transgenic expression of PGC1α in skeletal muscle (MCK‐PGC1α) protects against age‐dependent L‐Kyn associated pathology in a cohort of aging MCK‐PGC1α transgenic mice and their wildtype littermates of both sexes (n = 262). Physical function was assessed longitudinally from 16 to 24 months of age using treadmill endurance capacity, grip strength, walking speed and daily physical activity. Muscle function was assessed in situ using nerve‐mediated contraction of the soleus muscle. Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.

MCK‐PGC1α transgenic mice had significantly higher KAT expression ~2–5‐fold compared with wildtype littermates (p < 0.0001 for all isoforms). A main effect of L‐Kyn diet was observed for decreasing treadmill endurance capacity and daily physical activity in male mice (p ≦ 0.002). A main effect of L‐Kyn diet for decreasing maximal walking speed only was found in female mice (p = 0.037). Correspondingly, L‐Kyn increased frailty prevalence in male (+17%) and female (+26%) wildtype mice (p = 0.025 and 0.0001 respectively), which was mitigated by MCK‐PGC1α in both sexes. Soleus muscle strength and power were not impacted by diet or genotype in either sex (p > 0.5). Mitochondrial oxidative phosphorylation function in male and female MCK‐PGC1α mice was greater than wild type mice regardless of diet (p < 0.04), which is likely driven by upregulated expression of mitochondrial biogenesis related genes.

We conclude that PGC1α overexpression in skeletal muscle mitigates the exacerbation of physical frailty induced by elevated circulating L‐Kyn in aging mice, in part through increased skeletal muscle capacity for L‐Kyn metabolism due to PGC1α‐induced increase in muscle KAT expression.