Burnes LA, Kolker SJ, Danielson JF, Walder RY, Sluka KA. Enhanced muscle fatigue occurs in male but not female ASIC3Ϫ/Ϫ mice. Am J Physiol Regul Integr Comp Physiol 294: R1347-R1355, 2008. First published February 27, 2008 doi:10.1152/ajpregu.00687.2007.-Muscle fatigue is associated with a number of clinical diseases, including chronic pain conditions. Decreases in extracellular pH activates acid-sensing ion channel 3 (ASIC3), depolarizes muscle, protects against fatigue, and produces pain. We examined whether ASIC3Ϫ/Ϫ mice were more fatigable than ASIC3ϩ/ϩ mice in a task-dependent manner. We developed two exercise protocols to measure exercise-induced muscle fatigue: ( fatigue task 1, three 1-h runs; fatigue task 2, three 30-min runs). In fatigue task 1, male ASIC3ϩ/ϩ mice muscle showed less fatigue than male ASIC3Ϫ/Ϫ mice and female ASIC3ϩ/ϩ mice. No differences in fatigue were observed in fatigue task 2. We then tested whether the development of muscle fatigue was dependent on sex and modulated by testosterone. Female ASIC3ϩ/ϩ mice that were ovariectomized and administered testosterone developed less muscle fatigue than female ASIC3ϩ/ϩ mice and behaved similarly to male ASIC3ϩ/ϩ mice. However, testosterone was unable to rescue the muscle fatigue responses in ovariectomized ASIC3Ϫ/Ϫ mice. Plasma levels of testosterone from male ASIC3Ϫ/Ϫ mice were significantly lower than in male ASIC3ϩ/ϩ mice and were similar to female ASIC3ϩ/ϩ mice. Muscle fiber types, measured by counting ATPase-stained whole muscle sections, were similar in calf muscles from male and female ASIC3ϩ/ϩ mice. These data suggest that both ASIC3 and testosterone are necessary to protect against muscle fatigue in a task-dependent manner. Also, differences in expression of ASIC3 and the development of exercise-induced fatigue could explain the female predominance in clinical syndromes of pain that include muscle fatigue.
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