Roles of Histamine in Exercise-Induced Fatigue: Favouring Endurance and Protecting against Exhaustion

Abstract

Exercise necessitates a large supply of O 2 and nutrients and rapid removal of CO 2 and waste products. Histamine is a regulator of the microcirculation (which performs these exchanges), suggesting a possible involvement of histamine in exercise. Histamine is released from either mast cells or non-mast cells. In the latter, histamine is newly formed via the induction of histidine decarboxylase (HDC) in response to an appropriate stimulus, and it is released without being stored. Here, in mice, we examined the role of histamine or HDC induction in exercise. Prolonged walking (PW) (in a cylindrical cage turned electrically) increased HDC mRNA and HDC activity in quadriceps femoris muscles. Mice given a histamine H1-receptor antagonist [fexofenadine (peripherally acting) or pyrilamine (peripherally and centrally acting)] or an irreversible HDC inhibitor (α-fluoromethylhistidine) displayed less PW endurance than control mice. Ranitidine (H2-receptor antagonist) tended to reduce endurance. Other histamine-receptor (H3 and H4) antagonists had no significant effects on endurance. Mice deficient in HDC or histamine H1-receptors displayed markedly less endurance than control mice, and HDC activity in the quadriceps femoris of H1-deficient mice was rapidly elevated by PW. Fexofenadine significantly reduced the muscle levels of nitric oxide (NO) metabolites and glycogen after PW. The results support the ideas that (i) histamine is involved in protecting against exerciseinduced fatigue or exhaustion, (ii) histamine exerts its protective effect via H1 receptors and the ensuing production of NO in skeletal muscle, and (iii) histamine is provided, at least in part, by HDC induction in skeletal muscles during prolonged exercise.

Induction of the Histamine-Forming Enzyme Histidine Decarboxylase in Skeletal Muscles by Prolonged Muscular Work: Histological Demonstration and Mediation by Cytokines

“…9,10,[14][15][16] To extend those observations, in the present study we histologically confirmed the induction of HDC protein by PMW. Immunostaining of HDC in mouse gastrocnemius muscle clearly indicated that PMW increases HDCpositive cells (Figs.…”

“…9,10) In the present study, by immunostaining skeletal muscles using a recently introduced commercial polyclonal anti-HDC antibody, we found that cells in the endomysium and around blood vessels, and indeed some muscle fibers themselves, became HDCpositive after PMW. In normal mice, the amount of histamine in the skeletal muscles, as in skin, is much higher (about 100 times) than that found in mast cell-deficient mice, 14) suggesting that skeletal muscles are rich in mast cells.…”

“…9,10) In humans, histamine H1-and H2-receptors have been shown to be involved in mediating post-exercise hyperemia and vasodilation in skeletal muscles. 11,12) These findings suggested that histamine might support PMW by maintaining or enhancing the functions of the microcirculation.…”

“…8) Recent studies suggest that histamine may play important physiological roles in skeletal muscles. [9][10][11][12] Interestingly, PMW induces HDC in skeletal muscles in mice. [13][14][15][16] However, published histological analyses of such HDC induction are lacking because appropriate anti-HDC antibodies have not previously been available.…”

Analgesic Effects of 1st Generation Anti-histamines in Mice

“…6) It is notable that muscle fatigue and pain are common factors among TMD, OP, and OA, and that histamine has been suggested to be causally involved in muscle fatigue and pain. [7][8][9] Collectively, these reports encourage the view that 1st AHs may indeed exert analgesic effects in patients with TMD, OP, and/or OA.…”