Advance the understanding of mechanisms regulating sex differences in response to exercise

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Topic Description

Post Date: August 17, 2026

Expiration Date: August 17, 2028

The purpose of this topic is to leverage the sex differences data from Molecular Transducers of Physical Activity (MoTrPAC) studies or other large, publicly accessible datasets to advance the understanding of the impact of these differences on human physiology. 

Sex is a major modifier of the causes of death and morbidity, significantly influencing physiology and disease. Many chronic diseases that significantly impact U.S. healthcare costs—such as cancers, heart diseases, diabetes, osteoarthritis, osteoporosis, auto-immune diseases, and Alzheimer's disease—often disproportionately affect women. Despite the implementation of the NIH policy on Sex as a Biological Variable (NOT-OD-15-102), most clinical diagnostics remain predominantly based on data generated from male participants. Not surprisingly, 80% of drugs withdrawn from the market between 1997 and 2000 were removed due to adverse effects observed in women (Gilmer et al., 2023). This emphasizes the fundamental need to understand how sex differences affect normal physiology.

NIH Common Fund designed a clinical and preclinical study to identify the responses to exercise (Acute and Training). The preclinical study performed multi-omics analyses on 19 tissues/organs from rats of both sexes at 6 and 18 months of age. The results indicate that all organs have a response to exercise. In addition, and more surprisingly, there were varying degrees of sex differences in all organs examined (Many et al., 2024; MoTrPAC Study Group, 2024). This highlights the extreme importance of understanding the mechanisms driving these differences to enable improvements in health and eventually lead to more targeted drug development to treat human diseases. The wide range of the sex differences between organs suggests that tissue-specific factors may be involved. What are the implications of these differences for our understanding of integrated physiological function in humans? How can we use this new and emerging information to provide improved health for all?

References:

Gilmer G, Hettinger ZR, Tuakli-Wosornu Y, et al. Female aging: when translational models don't translate. Nat Aging. 2023;3(12):1500-1508. doi:10.1038/s43587-023-00509-8.

Many GM, Sanford JA, Sagendorf TJ, et al. Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue. Nat Metab. 2024;6(5):963-979. doi:10.1038/s42255-023-00959-9.

MoTrPAC Study Group; Lead Analysts; MoTrPAC Study Group. Temporal dynamics of the multi-omic response to endurance exercise training. Nature. 2024;629(8010):174-183. doi:10.1038/s41586-023-06877-w. 

Participating ICOs

National Institute on Aging (NIA)

Scientific questions of interest in this topic include, but are not limited to, the following:

  • What pathways are involved in regulating sex differences?
  • Are the pathways similar for all organs?
  • What molecular mechanisms are involved in sex-specific responses?
  • What are the temporal dynamics of sex differences in acute versus training responses?
  • How do aging, life stage, or reproductive status influence sex-dependent exercise responses?
  • Do sex differences in exercise-induced molecular adaptations intersect with pathways implicated in chronic diseases?
  • Can conserved sex-dependent molecular signatures be identified between animal models and humans?
ICO Scientific Contact:
Fei Wang, Ph.D.
[email protected]

Amanda Boyce, Ph.D.
[email protected]

John Williams, Ph.D.
[email protected]

Office of Research on Women's Health (ORWH)

The NIH Office of Research on Women’s Health (ORWH) seeks applications that advance understanding of mechanisms underlying sex differences in exercise responses across the life course. Consistent with NIH’s Sex as a Biological Variable (SABV) policy, ORWH encourages studies that use MoTrPAC to identify sex-dependent pathways relevant to conditions that predominantly or disproportionately affect women, including heart disease, autoimmune diseases, and Alzheimer’s disease.

Areas of interest include studies that:

  • Investigate sex differences across tissues and organ systems in medical conditions that predominantly affect women
  • Identify cellular and molecular mechanisms underlying sex-dependent exercise responses at the intersection of age, hormone dynamics, and reproductive status.
  • Link exercise adaptations to women’s health and precision prevention or treatment strategies.
  • Encourages curation of public datasets to advance the understanding of sex differences in health and disease.
This office does not award grants. Applications must be relevant to the objectives of at least one of the participating Institutes or Centers listed in this topic.
ICO Scientific Contact:
Rajeev K. Agarwal, Ph.D.
[email protected]

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