title: Enhanced muscle fatigue occurs in male but not female ASIC3-/- mice.
abstract: 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.
authors.affiliation: Graduate Program in Physical Therapy and Rehabilitation Science, Pain Research Program, Neuroscience Graduate Program, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Burnes
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Kolker
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Danielson
authors.forename: Roxanne Y
authors.initials: RY
authors.lastname: Walder
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sluka
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D018763:Muscle Fatigue; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D010052:Ovariectomy; D010146:Pain / Q000378:metabolism; D005082:Physical Exertion; D012420:Running; D012737:Sex Factors; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*
chemical_list: C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D015222:Sodium Channels; D013739:Testosterone