03 May 2024

We all know that physical activity is good for us, and may even help stave off dementia. But what are the underlying molecular mechanisms? Understanding how exercise affects the entire body at the transcriptomic, proteomic, epigenetic, and metabolomic level is the goal of the molecular transducers of physical activity in humans consortium (MoTrPAC), a 10-year project funded by the NIH Common Fund in 2016. Pronounced “motor pack,” the $170 million grant supports exercise studies in humans and rats, both of which involve extensive fluid and tissue sampling to study the molecular manifestations of acute and endurance exercise across multiple organs (Sanford et al., 2020; MoTrPAC study group, 2024). Eight years in, with human studies ongoing, the first set of rat findings are now published. One paper in Nature maps molecular responses to endurance training across 18 organs, including the brain and the cardiovascular system. Another, in Nature Communications, reports that endurance training influences the expression of disease-associated genes, including those implicated in asthma. A third, published in Nature Metabolism, identified sex differences in how fat tissue responds to training, with males burning more fat than females.

Deep Dive into Exercise. MoTrPAC studies rodents and people, with harmonized protocols and centralized centers for chemical and omics analyses. [Courtesy of Sanford et al., 2020.]

Scientists have been trying to understand if and how physical activity mitigates dementia risk for decades, and though benefits are implied, the underlying mechanisms remain murky (for example, Mar 2018 news; Jul 2022 news; Mar 2023 news). The hope is that MoTrPAC will help fill in some of the missing pieces of the puzzle, and inform personalized exercise interventions to thwart disease.

MoTrPAC’s flagship study, reported in Nature, surveyed body-wide molecular responses to progressive endurance training. Sue Bodine of the Oklahoma Medical Research Foundation in Oklahoma City co-led the work with Steven Carr of the Broad Institute of MIT and Harvard in Boston, Karyn Esser of the University of Florida in Gainesville, Simon Schenk of the University of California, San Diego, and Stanford University scientists Stephen Montgomery, Michael Snyder, and Matthew Wheeler. Six-month-old rats were either left to a sedentary lifestyle, without access to a treadmill, or they were put on an endurance training program, in which they ran on a treadmill five days per week for one, two, four, or eight weeks. As training progressed, running time increased from 20 to a maximum of 50 minutes and the incline made steeper (image above). Two days after the last exercise session, the researchers collected blood, plasma, and 18 solid organs, with the cortex, hippocampus, and hypothalamus representing the brain. The researchers then subjected the samples to a barrage of molecular analyses, with the most abundant and biologically relevant tissues, such as the calf muscle, heart, liver, and white adipose tissue, undergoing the most diverse array of tests (image below).

Whole Body Workout. Two days after the last treadmill session, blood, plasma, and 18 solid organs were harvested (left) and subjected to multi-omic analyses (labeled on right). [Courtesy of MoTrPAC study group, Nature, 2024.]

What did this sweeping analysis uncover? In a nutshell, exercise provoked a mind-boggling array of molecular changes across the entire body. Some, such as upregulation of heat shock proteins, were shared across tissues, suggesting common responses, while others, such as changes related to immune cell recruitment and tissue remodeling in the lung, cholesterol biosynthesis in the liver, and ion flux in the heart, only happened in one or a few organs. Some of these molecular responses rose or fell as endurance training progressed.

In the hippocampus, eight weeks of training triggered a boost in transcripts involved in neuroplasticity. This included transcripts encoding the NMDA receptor subunit Grin2d, as well as the BDNF receptor. The latter finding jibes with previous studies, which reported that BDNF levels rise in response to exercise, and may stave off cognitive decline by promoting the growth and function of neurons in the hippocampus (May 2002 news; Sep 2018 news). 

More than half of the molecular responses differed by sex, particularly in the adrenal glands and subcutaneous fat. Though all tissues showed changes in response to exercise, some were more responsive than others. For example, the transcriptomes of the blood, brown and white fat, adrenal gland, and colon changed dramatically, while only small shifts in gene expression took place in the hypothalamus, cortex, testes, and vena cava. For proteomics, the calf muscle, heart, and liver had the most robust changes.

“The vast number of differential features over the training time course across tissues and omes highlights the multi-faceted, organism-wide nature of molecular adaptations to endurance training,” the authors wrote.

The findings also underscore the relationship between physical activity and disease prevention. For example, downregulated genes from fat, kidney, and liver included those implicated in Type 2 diabetes, cardiovascular disease, obesity, and kidney disease. This link between exercise and disease prevention was supported by a separate MoTrPAC study led by Montgomery and published in Nature Communications. There, the researchers identified more than 5,500 disease-related genes that changed in response to endurance training in specific tissues. For example, expression of low-density lipoprotein receptor (LDLR), a gene in which loss-of-function variants cause familial hypercholesterolemia, rose in the cortex, hippocampus, and skeletal muscle in response to endurance training. This receptor helps clear low-density lipoproteins, aka “bad” cholesterol, suggesting that exercise might bolster this protective function. Both high cholesterol and low expression of LDLR in the brain have been implicated in AD. Notably, LDLR also binds ApoE, and supports clearance of Aβ and tau deposits (Kim et al., 2009; Jul 2021 news).

The third paper in Nature Metabolomics zeroed in on sex-specific responses in subcutaneous white adipose tissue. Even in a sedentary state, the fat of male rats was steeped in markers of aerobic metabolism and lipid utilization. This profile was enhanced by training, which could explain why male rats lost fat stores over eight weeks of working out. Females didn’t, and their fat was enriched in markers of adipogenesis and insulin signaling, which only increased with training. The findings suggest that exercise interventions—particularly those aimed at reducing obesity or metabolic disorders—need to take sex into account.

Researchers have long puzzled over whether the benefits of physical activity on cognition and memory might be due to a direct effect on the brain, and/or to improvements in other tissues, such as the cardiovascular and immune systems. This resource could help them tease apart these effects, and point to the most optimal exercise interventions. Scientists interested in how specific tissues respond to endurance training can now access this omics dataset online, at https://motrpac-data.org/.—Jessica Shugart

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References

News Citations

1. 44-Year Study Ties Midlife Fitness to Lower Dementia Risk 28 Mar 2018
2. In the U.S., 40 Percent of All-Cause Dementia Is Preventable 14 Jul 2022
3. Exercise May Not Keep People Sharp After All, Meta-Analysis Says 31 Mar 2023
4. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis 22 Nov 2002
5. Exercise Pill? Pharmacological Mimics Boost Cognition in Lazy Mice 9 Sep 2018
6. Mind Over Heart—LDL Receptors Crimp ApoE, Aβ Accumulation 11 Dec 2009
7. Taming ApoE Via the LDL Receptor Calms Microglia, Slows Degeneration 2 Jul 2021

Paper Citations

1. Sanford JA, Nogiec CD, Lindholm ME, Adkins JN, Amar D, Dasari S, Drugan JK, Fernández FM, Radom-Aizik S, Schenk S, Snyder MP, Tracy RP, Vanderboom P, Trappe S, Walsh MJ, Molecular Transducers of Physical Activity Consortium. Molecular Transducers of Physical Activity Consortium (MoTrPAC): Mapping the Dynamic Responses to Exercise. Cell. 2020 Jun 25;181(7):1464-1474. PubMed.
2. MoTrPAC Study Group. Molecular Transducers of Physical Activity Consortium (MoTrPAC): Human Studies Design and Protocol. J Appl Physiol (1985). 2024 Apr 18; PubMed.

External Citations

1. https://motrpac-data.org/

Further Reading

News

1. Exercise Linked to Less Pathology, Better Function in Familial AD 27 Sep 2018
2. Sit Less, Move More to Induce Irisin and Stave Off Dementia 14 Sep 2023
3. Light Is Alright: Mild Physical Activity Comes With Larger Brain 26 Apr 2019