Skeletal Muscle PGC-1 α Alleviates Age-Related Declines in Physical Function by Modulating L-Kynurenine Metabolism

BACKGROUND: Aging is associated with deterioration of metabolic, physical, and physiological functions, resulting in a profound impact on quality of life. L-Kynurenine (L-Kyn) is a product of tryptophan catabolism which increases with age and has been associated with frailty in humans. Regulated by the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), kynurenine aminotransferases (KATs) are responsible for degrading L-Kyn into kynurenic acid and are robustly expressed in skeletal muscle. OBJECTIVE: The objective of this study was to 1) determine if elevating L-Kyn levels exacerbates an age-related decline in physical, muscle, and mitochondrial functions, and 2) determine if transgenic expression of PGC1α in skeletal muscle (MCK-PGC1α) protects against age-dependent L-Kyn associated pathology. METHODS: Male and female 16-mo C57BL6N (wildtype; WT) and MCK-PGC1α mice were randomized to either a control diet or diet supplemented with 200mg/kg L-Kyn. Physical function was assessed using a battery of tests including treadmill running capacity, physical activity, walking speed, and grip strength at 16, 20, and 24 mos. of age. Terminal experiments were performed within 2 wks after the physical function assessment at 24 mo. RESULTS: As expected, both male and female mice displayed significant age-dependent declines in all metrics of physical function. In male mice, L-Kyn supplementation significantly decreased running capacity ( P =0.002) and physical activity ( P <0.0001). In females, L-Kyn only decreased walking speed ( P <0.04). Female MCK-PGC1α mice demonstrated greater running capacity, physical activity, and walking speed than WT regardless of diet or age ( P <0.006). Soleus muscle strength and power were not impacted by diet or genotype in males ( P =0.12) or females ( P =0.16). Mitochondrial oxidative phosphorylation (OXPHOS) function in male MCK-PGC1α was 36% greater than WT ( P =0.04) while there was a ~41% increase in female MCK-PGC1α relative to WT ( P <0.01). No effect of L-Kyn was detected on OXPHOS ( P =0.22). CONCLUSION: Age-related declines in running capacity, physical activity levels, and walking speed are exacerbated by increased L-Kyn levels. Elevating KAT expression through transgenic expression of PGC1α in skeletal muscle can mitigate some of these effects, highlighting muscle as a key source of L-Kyn catabolism. This study was supported by the National Institutes of Health grant R01-AG076490 (T.E.R and R.T.H). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.