The beneficial effects of physical activity (PA) are well documented, yet the mechanisms by which PA prevents disease and improves health outcomes are poorly understood. To identify major gaps in knowledge and potential strategies for catalyzing progress in the field, the NIH convened a workshop in late October 2014 entitled "Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits." Presentations and discussions emphasized the challenges imposed by the integrative and intermittent nature of PA, the tremendous discovery potential of applying "-omics" technologies to understand interorgan crosstalk and biological networking systems during PA, and the need to establish an infrastructure of clinical trial sites with sufficient expertise to incorporate mechanistic outcome measures into adequately sized human PA trials. Identification of the mechanisms that underlie the link between PA and improved health holds extraordinary promise for discovery of novel therapeutic targets and development of personalized exercise medicine.

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

Nitrogen (N) balance, fed-state leucine kinetics, and urinary 3-methylhistidine (3-MeH) excretion were examined in 12 men and women, aged 56-80 yr, before and during 12 wk of resistance training (RT). Subjects were randomized to groups that consumed diets providing either 0.80 +/- 0.02 g protein.kg-1.day-1 (lower protein, LP) or 1.62 +/- 0.02 g protein.kg-1.day-1 (higher protein, HP). At baseline, mean N balance was negative for LP (-4.6 +/- 3.4 mg N.kg-1.day-1) and positive for HP (13.6 +/- 1.0 mg N.kg-1.day-1). N retention increased similarly in LP and HP at the 11th wk of RT by 12.8 and 12.7 mg N.kg-1.day-1, respectively. Thus LP had an increased efficiency of N retention. LP had decreased leucine flux (P < 0.001), oxidation (P < 0.001), and uptake for protein synthesis (P < 0.02), relative to HP, both at baseline and after RT. Leucine flux increased with RT in both diet groups (P < 0.05) and was associated mainly with an increase in protein synthesis in LP (91% of change in flux) and an increase in oxidation in HP (72% of change in flux; RT-diet interaction, P < 0.05). RT increased actomyosin protein breakdown (increased 3-MeH-to-creatinine ratio, P < 0.01). Diet-related differences in protein metabolism did not influence body composition changes with RT. These data show that the efficiency of N retention and protein utilization during RT is higher in older subjects who consume 0.8 vs. 1.6 g protein.kg-1.day-1 dietary protein.