Heat-induced calcium leakage causes mitochondrial damage in caenorhabditis elegans body-wall muscles

Kenta Momma, Takashi Homma, Ruri Isaka, Surabhi Sudevan, Atsushi Higashitani

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    Acute onset of organ failure in heatstroke is triggered by rhabdomyolysis of skeletal muscle. Here, we showed that elevated temperature increases free cytosolic Ca2+ [Ca2+ ]f from RYR (ryanodine receptor)/UNC-68 in vivo in the muscles of an experimental model animal, the nematode Caenorhabditis elegans. This subsequently leads to mitochondrial fragmentation and dysfunction, and breakdown of myofilaments similar to rhabdomyolysis. In addition, treatment with an inhibitor of RYR (dantrolene) or activation of FoxO (Forkhead box O)/DAF-16 is effective against heat-induced muscle damage. Acute onset of organ failure in heatstroke is triggered by rhabdomyolysis of skeletal muscle. To gain insight into heat-induced muscle breakdown, we investigated alterations of Ca2+ homeostasis and mitochondrial morphology in vivo in body-wall muscles of C. elegans exposed to elevated temperature. Heat stress for 3 hr at 35° increased the concentration of [Ca2+ ]f, and led to mitochondrial fragmentation and subsequent dysfunction in the muscle cells. A similar mitochondrial fragmentation phenotype is induced in the absence of heat stress by treatment with a calcium ionophore, ionomycin. Mutation of the unc-68 gene, which encodes the ryanodine receptor that is linked to Ca2+ release from the sarcoplasmic reticulum, could suppress the mitochondrial dysfunction, muscle degeneration, and reduced mobility and life span induced by heat stress. In addition, in a daf-2 mutant, in which the DAF-16/FoxO transcription factor is activated, resistance to calcium overload, mitochondrial fragmentation, and dysfunction was observed. These findings reveal that heat-induced Ca2+ accumulation causes mitochondrial damage and consequently induces muscle breakdown.

    元の言語English
    ページ(範囲)1985-1994
    ページ数10
    ジャーナルGenetics
    206
    発行部数4
    DOI
    出版物ステータスPublished - 2017 1 1

    ASJC Scopus subject areas

    • Genetics

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