Muscle-Specific Upregulation of Timeless Mediates Exercise-Induced Amelioration of Age-Related Circadian Rhythm Disruption and Cardiac Dysfunction in Drosophila.

Abstract

The core genes of the circadian pathway, such as Timeless(Tim), not only participate in the regulation of biological rhythms, but also play significant roles in DNA damage repair, chronic inflammation, and cellular metabolism. However, it remains unclear whether exercise can delay the age-related phenotypic degeneration by regulating the muscle Tim gene. In here, we first carried out the expression regulation of the muscle Tim gene in the Drosophila by constructing the Mhc-gal4/Tim-UAS system, and then subjected the flies to a 4-week endurance exercise intervention. The results showed that the knockdown of the muscle Tim gene accelerated aging-related phenotypic deterioration in Drosophila, manifesting as increased nighttime activity, decreased climbing speed, elevated heart rate and reduced stroke volume, shortened time to hypoxic heart failure, and shortened lifespan. This is accompanied by reductions in muscle tissue levels of the Clk gene, Sir2 gene, PGC-1α gene, Mhc gene, MRCC-I protein, and SOD protein, along with a significant increase in ROS. Conversely, overexpression of the muscle Tim gene delayed aging-related phenotypic changes in aged Drosophila. Exercise not only effectively counteracts the acceleration of aging-related phenotypic deterioration caused by muscle Tim gene knockdown but also further delayed aging-related phenotypic changes in aged Drosophila on the basis of muscle Tim gene overexpression. In summary, this study highlights the role of the muscle Tim gene in the aging of skeletal muscles and the heart, as well as the relationship between exercise and the muscle Tim gene, providing strategies for the prevention and treatment of age-related diseases.