The Response To Physical Activity In Mouse And Man: An Interplay Between Genetics And Exercise

Abstract

Increased physical activity is routinely prescribed by physicians as a defense to combat and prevent cardiometabolic diseases. Despite this, the molecular mechanisms by which participation in physical activity leads to improvements in health are unknown and needed for the development of personalized medicine and next generation therapeutic approaches. To address these needs, we undertook an unprecedented massive scale genetics project where female mice from the Hybrid Mouse Diversity Panel (HMDP) performed voluntary wheel running for approximately one month. The HMDP is a powerful and unique genetic tool that has been used in the intricate dissection of complex traits, especially cardiometabolic ones, and consists of over 100 inbred and recombinant inbred strains of mice. Twelve samples were taken from each animal resulting in thirty different traits allowing for a comprehensive whole-body and tissue specific assessment of the exercise response to be conducted. Furthermore, our exercise HMDP was integrated with the human Skeletal Muscle, Myokines and Glucose Metabolism (MyoGlu) study. This study consisted of twenty-six normal or overweight male Norwegians who were subjected to a 12-week exercise training program with pre- and post-acute exercise bouts. Subcutaneous white adipose tissue and skeletal muscle biopsies were taken at multiple time points within MyoGlu which nicely complement, substantiate, and expound upon our mouse data. Using a multi-tissue and multi-omics approach in mouse and man, our discoveries fit into four main categories: 1) phenotypic response to exercise for clinically and physiologically relevant traits (highlighted by reductions in liver triglycerides), 2) molecular response to exercise within skeletal muscle, white adipose tissue, brown adipose tissue, liver, and heart (distinct reprogramming of brown adipose tissue metabolism), 3) a personalized exercise response due to the interaction between exercise dose (duration, intensity, type) and natural genetic variation, and 4) insight into the biology of volitional exercise where strong central nervous system regulation was uncovered. Our results are also being made publicly available in a user friendly and simple web app designed to allow researchers to visualize, compare, and interrogate data at all levels.