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Enhanced muscle fatigue occurs in male but not female ASIC3–/– mice – Source: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, April 2008

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By Lynn A. Burnes, Kathleen A Sluka, et al. • • April 8, 2008

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 ASIC3–/– mice were more fatigable than ASIC3+/+ 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 ASIC3+/+ mice muscle showed less fatigue than male ASIC3–/– mice and female ASIC3+/+ 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 ASIC3+/+ mice that were ovariectomized and administered testosterone developed less muscle fatigue than female ASIC3+/+ mice and behaved similarly to male ASIC3+/+ mice.

However, testosterone was unable to rescue the muscle fatigue responses in ovariectomized ASIC3–/– mice. Plasma levels of testosterone from male ASIC3–/– mice were significantly lower than in male ASIC3+/+ mice and were similar to female ASIC3+/+ mice. Muscle fiber types, measured by counting ATPase-stained whole muscle sections, were similar in calf muscles from male and female ASIC3+/+ 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.

Source: American Journal of Physiology – Regulatory Integrative and Comparative Physiology, April 2008; 294(4):R1347-55. PMID: 18305024, Burnes LA, Kolker SJ, Danielson JF, Walder RY, Sluka KA. Graduate Program in Physical Therapy and Rehabilitation Science, Pain Research Program, Neuroscience Graduate Program, University of Iowa, Iowa City, Iowa, USA. [E-mail:]

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