The metabolic secrets of good runners
Chemical changes in runners linked to physical fitness.
A healthy heart and svelte physique are not the only physical changes wrought by exercise: researchers have also identified a host of metabolic changes that occur during exercise in physically fit athletes.
These changes, described today in Science Translational Medicine1, suggest that exercise revs up the pathways that break down stored sugars, lipids and amino acids, as well as improving blood-sugar control. The results might eventually lead to dietary supplements that boost athletic performance or invigorate patients suffering from debilitating diseases, says study author Robert Gerszten, a clinician scientist at Massachusetts General Hospital in Boston.
Metabolic profiling has lagged behind large-scale studies of gene and protein expression, in part because the collection of metabolites in the human body — sometimes referred to as the metabolome — is so complex. "The alphabet for the DNA world is four letters long, and for the protein world it's twenty amino acids," says David Wishart, a metabolomics researcher at the University of Alberta in Canada who was not involved with the new work. "The alphabet for metabolites is about 8,000 different compounds, so it's a tough language to learn."
Gerszten and his colleagues assayed 210 of these metabolites to fill a gap in our understanding of the effects of exercise. "It's well known that exercise protects against cardiovascular and metabolic diseases and predicts long-term survival," says Gerszten. "But how exercise confers its salutary effects is less understood."
Feel the burn
The team used mass spectrometry to measure changes in the metabolic profiles of 70 people before and after a ten-minute run on a treadmill. They detected changes in 21 compounds, including several not previously linked to exercise.
Some of these changes tended to be more extreme in study participants who had a greater peak oxygen intake — an indicator of physical fitness. Running the Boston Marathon also brought on some of these changes, particularly in those runners who finished the 26.2-mile course within four hours.
And samples from 302 participants in a large health study called the Framingham Heart Study indicated that the concentration of two metabolites associated with fitness — glycerol and glutamine — also varied with resting heart rate, another measure of physical fitness.
It is too soon to say whether these changes actually contribute to physical stamina — so far the study has shown only that the levels of these metabolites change. Gerszten says that his team is now addressing this lingering question using animal studies. But the team did feed muscle cells grown in culture a mixture of five metabolites that were all increased by running — glycerol, niacinamide, glucose-6-phosphate, pantothenate and succinate. In response, the cells immediately upped their expression of a protein called NUR77, which regulates the use of glucose and lipids in skeletal muscle.
The study was remarkably thorough, says Gary Siuzdak, senior director of the Center for Mass Spectrometry at the Scripps Research Institute in La Jolla, California. A valuable follow-up, he adds, would be to profile metabolites in an untargeted way rather than restricting the assay to the initial set of two hundred specific compounds. This approach is more difficult: researchers perform less-specific initial assays to look for differences in the chemical composition of their samples, and must then double-back to identify the chemicals, a process that Siuzdak describes as both "tedious" and "really quite daunting".
But the approach could be worth the trouble, he says. Siuzdak and his colleagues recently found that the balance of oxidized and reduced metabolites regulates stem-cell differentiation2 — an observation that, he says, they would have missed had they not taken an unbiased approach to looking for metabolic differences.
Meanwhile, Wishart says the work raises the bar for metabolic profiling because of the sheer number of metabolites assayed. The study should also serve as a reminder of the need to focus on metabolites, he adds. "In our hunt to find genes and proteins to explain everything, we often forget the importance of small molecules."
- Lewis, G. D. et al. Sci. Trans. Med. 2, 33ra37 (2010).
- Yanes, O. et al. Nature Chem. Biol. doi:10.1038/nchembio.364 (2010).