Copyright @ 200 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited. 8 Gender-Related Differences in Muscle Injury, Oxidative Stress, and Apoptosis CHAD KERKSICK 1,2 , LEM TAYLOR IV 3 , ALISON HARVEY 4 , and DARRYN WILLOUGHBY 5,6 1 Applied Biochemistry and Molecular Physiology Laboratory, Health and Exercise Science Department, University of Oklahoma, Norman, OK; 2 Section of Diabetes and Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK; 3 Department of Exercise & Sport Science, University of Mary Hardin-Baylor, Belton, TX; 4 Nutritional Sciences, Department of Human Ecology, The University of Texas at Austin, Austin, TX; 5 Exercise and Biochemical Nutrition Laboratory, Exercise Nutrition and Resistance Training Research Unit, Department of Health, Human Performance and Recreation, Baylor University, Waco, TX; and 6 Institute for Biomedical Studies, Baylor University, Waco, TX ABSTRACT KERKSICK, C., L. TAYLOR IV, A. HARVEY, and D. WILLOUGHBY. Gender-Related Differences in Muscle Injury, Oxidative Stress, and Apoptosis. Med. Sci. Sports Exerc., Vol. 40, No. 10, pp. 1772–1780, 2008. Due to its alleged antioxidant properties, 17A- estradiol (E 2 ) may protect against muscle injury, oxidative stress, and apoptosis. Purpose: This study sought to determine whether such mechanisms existed between genders for muscle injury, oxidative stress, and apoptosis after eccentric exercise. Methods: Eight men and eight women (no oral contraceptive use; midluteal phase of menstrual cycle) performed 7 Â 10 eccentric repetitions of the knee extensors at 150% 1RM. Strength, soreness, and blood samples were taken before exercise and 6, 24, 48, and 72 h after exercise while muscle samples were collected before and 6 and 24 h after exercise. Blood samples were assayed for free E 2 , lactate dehydrogenase (LDH), superoxide dismutase (SOD), and 8-isoprostane (8-iso). Muscle samples were assayed for mitochondrial apoptosis (e.g., bax, bcl-2, cytochrome c, and cell death), total DNA content, and myofibrillar protein content. Results: Men reported greater soreness levels at 24, 48, and 72 h after exercise, whereas strength changes were similar among genders. At baseline and independent of exercise, females had higher E 2 (P G 0.001) and SOD in conjunction with lower 8-iso levels when compared with men. Bax increased in both genders, whereas bcl-2 increased only in women with no cytochrome c changes for either gender after exercise. The bax/bcl-2 ratio in women significantly decreased after 6 h (P = 0.03) and returned to baseline levels after 24 h. Men exhibited greater cell death at all time points (P G 0.05), whereas myofibrillar protein content and total DNA content decreased in both genders at 24 h after exercise. No changes in LDH were found (P 9 0.05). Conclusions: Although more research is needed, differences between gender may provide greater endogenous protection against oxidative stress and apoptosis. Key Words: ESTROGEN, ECCENTRIC EXERCISE, MUSCLE DAMAGE, CELL DEATH, ANTIOXIDANT T hroughout the last decade, researchers have inves- tigated the impact of gender on exercise-induced muscle damage and associated postdamage intra- muscular responses. Although some debate remains toward the impact of gender, evidence exists to suggest that gender may impact the physiological response to damaging exercise (27). The primary female sex hormone, 17A- estradiol (E 2 ), centers this debate and is purported to have potent antioxidant properties and subsequent impact on the degree of exercise-induced muscle damage, in addition to the postexercise inflammatory and repair processes (11). Limited investigations, however, have reported on the nature to which E 2 can attenuate muscle damage and antioxidative activities after a bout of eccentric muscle contractions. Using animal and human models, the impact of E 2 on markers of inflammation and muscle damage during continuous bouts of moderate-intensity aerobic exercise (30–90 min at 60–70% V ˙ O 2max ) has been reported. In men, an 8-d supplementation period with E 2 had no impact on inflammatory responses to acute exercise (35). In women, however, an attenuation of circulating IL-6 (a proinflamma- tory cytokine) was found to be dependent of the menstrual cycle phase and oral contraceptive use after an acute cycling exercise (34). Similarly, Carter et al. (5) concluded that serum creatine kinase (CK) was significantly reduced 72 h after 30 min of downhill running in women taking oral contraceptives and tested during their midluteal phase (high E 2 ) when compared with eumenorrheic women not taking oral contraceptives and tested during their midfollicular phase (low E 2 ) (5). Furthermore, Tiidus et al. (33) reported significantly lower levels of intramuscular neutrophils and Address for correspondence: Darryn Willoughby, Ph.D., FACSM, Exercise and Biochemical Nutrition Laboratory, PO Box 79713, Baylor University, Waco, TX 76798-7313; E-mail: Darryn_Willougbhy@baylor.edu. Submitted for publication February 2008. Accepted for publication April 2008. 0195-9131/08/4010-1772/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE Ò Copyright Ó 2008 by the American College of Sports Medicine DOI: 10.1249/MSS.0b013e31817d1cce 1772 BASIC SCIENCES