Considerations for Sex-Cognizant Research in Exercise Biology and Medicine

Abstract

As the fields of kinesiology, exercise science, and human movement developed, the majority of the research focused on male physiology and extrapolated findings to females. In the medical sphere, basing practice on data developed in only males resulted in the removal of drugs from the market in the late 1990s due to severe side effects (some life-threatening) in females that were not observed in males. In response to substantial evidence demonstrating exercise-induced health benefits, exercise is often promoted as a key modality in disease prevention, management, and rehabilitation. However, much like the early days of drug development, a historical literature knowledge base of predominantly male studies may leave the exercise field vulnerable to overlooking potentially key biological differences in males and females that may be important to consider in prescribing exercise (e.g., how exercise responses may differ between sexes and whether there are optimal approaches to consider for females that differ from conventional approaches that are based on male physiology). Thus, this review will discuss anatomical, physiological, and skeletal muscle molecular differences that may contribute to sex differences in exercise responses, as well as clinical considerations based on this knowledge in athletic and general populations over the continuum of age. Finally, this review summarizes the current gaps in knowledge, highlights the areas ripe for future research, and considerations for sex-cognizant research in exercise fields.

Keywords: exercise medicine; molecular biology; muscle; physiology; sex differences.

Figure 1

(A) Depicts the standardly accepted 28-day menstrual cycle. (B) The different ranges of real-world normal cycles (experiencing proper hormone fluctuations). From outer to inner ring: 36–50 days (avg. 40 depicted) with ovulation at 26.8 days (67% follicular). 31–35 days (avg. 32 days)–ovulation at 19.5 days (61% follicular). 25–30 days (avg. 28 days follicular) with ovulation at 15.2 days (54% follicular). 21–24 days (avg. 23 days) with ovulation at 12.4 days (54% follicular). Finally, 15–20 days (avg. 18 days) with ovulation at 10.4 days (57% follicular). Created with BioRender.com.

Figure 2

Normal hormone concentration ranges depicted in ng/mL for visual comparison between the sexes. Female ranges depict the low to high values experienced throughout the menstrual cycle.

Figure 3

Schematic of the reduction in sex differences reported in the literature (throughout text) with increasing physical activity levels. Created with BioRender.com.

Figure 4

The commonly understood electron transport chain, simplified (male), results in ROS buildup, a consequence of increased O2 diffusion into the mitochondria and subsequent consumption by CIV, greater ADP influx (due to greater ADP sensitivity) and ATP production. The parallel pathway (female) is depicted, however the degree in which it functions over or in conjunction with the common pathway (male) is not fully understood. Briefly: Decreased O2 consumption in peripheral tissues may have induced adaptation of mitochondria in females to require more efficient control of energy production, as evidenced by human and animal studies (in text). Decreased ADP sensitivity (sex differences in VDAC and ANT regulation unknown) in females would prevent large influx of ADP from the cytosol, reducing the production of ROS overall. Estrogen represses Ucp3 expression, preventing energy dissipation, and reduces proton transport into the mitochondria, a possible strategy for energy conservation and a response to decreased ROS production. Increased Malonyl-CoA production, inhibits CPT1 transport of free fatty acids into the mitochondria, resulting in greater triglyceride production in the cytosol and a more controlled energy production within the mitochondria. Greater CII involvement (female), requiring less proton influx may control production of ROS further. Overall, these adaptations suggest that females exhibit an efficient control of ATP production while simultaneously reducing ROS production. Created with BioRender.com. ADP, adenosine diphosphate; ATP, adenosine triphosphate; ANT, adenosine nucleotide translocase; VDAC, voltage-dependent anion channel; CC, cytochrome c; UCP3, uncoupling protein 3; CPT1, carnitine palmitoyltransferase; Complex I, II, II, IV; E2, estradiol; FFA, free fatty acid; ER-beta, estrogen receptor beta; NAD+, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; Q, coenzyme Q; H+, proton.