Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

Abstract

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.

Regular physical activity prevents development of chronic pain and activation of central neurons

“…Hindpaw and forepaw grip force was tested before and after 5 days (n ϭ 4) or 8 wk (n ϭ 8) of running wheel activity and compared with sedentary mice (n ϭ 8) as previously described (6). The mice were familiarized twice per day for 2 days to the apparatus by performing the grip force task (San Diego Instruments, San Diego, CA, http://www.sandiegoinstruments.com).…”

ASIC3 Channels in Multimodal Sensory Perception

“…Also, the cytoplasmic level of testosterone from male asic3 -/-mice was significantly lower than that in WT male mice and was similarly low in female WT mice. These data suggest that both ASIC3 and testosterone are necessary for protecting against muscle fatigue (61). Moreover, differences in the expression of ASIC3 and the development of exercise-induced fatigue could explain the female predominance in clinical syndromes of pain that include muscle fatigue (61 Review are unclear but could involve decreases in extracellular pH, activation of ASIC3 channels, and subsequent muscle depolarization, which protects against fatigue or causes pain sensation.…”

“…These data suggest that both ASIC3 and testosterone are necessary for protecting against muscle fatigue (61). Moreover, differences in the expression of ASIC3 and the development of exercise-induced fatigue could explain the female predominance in clinical syndromes of pain that include muscle fatigue (61 Review are unclear but could involve decreases in extracellular pH, activation of ASIC3 channels, and subsequent muscle depolarization, which protects against fatigue or causes pain sensation. Moderate exercise increases the expression of asic3 mRNA in chronic fatigue syndrome patients but not in normal subjects (62).…”

“…Burnes et al (61) examined the role of ASIC3 in the development of muscle fatigue. Using exercise protocols to measure exercise-induced muscle fatigue, they found that enhanced muscle fatigue occurs in male but not female asic3 -/-mice in a task-dependent manner (61). Moreover, WT female mice that were ovariectomized and administered testosterone developed less muscle fatigue than control female mice and behaved similarly to WT male mice.…”

Expression of acid-sensing ion channels in nucleus pulposus cells of the human intervertebral disk is regulated by non-steroid anti-inflammatory drugs

“…Recently, Cuesta et al [17] showed the presence and localization of different ASICs in the human healthy intervertebral disk, and an increased expression of ASICs in the degenerated intervertebral disk, indicating that ASICs may be involved in intervertebral disk degeneration. In this study, we investigated two ASIC subunits (ASIC1 and ASIC3) in nucleus pulposus cells of the human intervertebral disk, which were reported to be relevant for the function of connective tissues including bone and cartilage [18][19][20]. Uchiyama et al [21] confirmed the presence of ASIC3 subunit in nucleus cells of the intervertebral disk.…”