New insights into the cellular and molecular mechanisms of skeletal muscle fatigue, 2024, Edward P. Debold

New insights into the cellular and molecular mechanisms of skeletal muscle fatigue: The Marion J. Siegman Award Lectureships

Abstract
Skeletal muscle fibers need to have mechanisms to decrease energy consumption during intense physical exercise to avoid devastatingly low ATP levels, with the formation of rigor cross-bridges and defective ion pumping. These protective mechanisms inevitably lead to declining contractile function in response to intense exercise, characterizing fatigue.

Through our work we have gained insights into cellular and molecular mechanisms underlying the decline in contractile function during acute fatigue. Key mechanistic insights have been gained from studies performed on intact and skinned single muscle fibers, and more recently from studies performed and single myosin molecules.

Studies on intact single fibers revealed several mechanisms of impaired sarcoplasmic reticulum (SR) Ca2+ release and experiments on single myosin molecules provide direct evidence of how putative agents of fatigue impact myosin's ability to generate force and motion. We conclude that changes in metabolites due to an increased dependency on anaerobic metabolism (e.g. accumulation of inorganic phosphate ions and H+) act to directly and indirectly (i.e. via decreased Ca2+ activation) inhibit myosin's force and motion generating capacity.

These insights into the acute mechanisms of fatigue may help improve endurance training strategies and reveal potential targets for therapies to attenuate fatigue in chronic diseases.

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