{"doi":"10.7275/13657924","title":"Mechanisms and Mitigation of Skeletal Muscle Fatigue in Single Fibers from Older Adults","abstract":"Skeletal muscle fatigue is the contraction-induced decline in whole muscle force or power, and can be greater in older versus young adults. Fatigue primarily results from increased metabolism elevating phosphate (P<sub>i</sub>) and hydrogen (H<sup>+</sup>), which alters myosin-actin interactions; however, which steps of the myosin-actin cross-bridge cycle are changed and their reversibility are unclear. <strong>PURPOSE: </strong>This study sought to: 1) Examine the effects of elevated P<sub>i</sub> and H<sup>+</sup> on molecular and cellular function, and 2) Test the ability of deoxyadenosine triphosphate (dATP), an alternative energy to adenosine triphosphate (ATP), to reverse the contractile changes induced with high P<sub>i</sub> and H<sup>+</sup>. <strong>METHODS:</strong> Maximal tension (force/cross-sectional area), myofilament mechanics and myosin-actin cross-bridge kinetics were measured in 214 single fibers (104 type 1) from the vastus lateralis of eight (4 men) healthy, sedentary older adults (71<strong>±</strong>1.3 years) under normal (5 mM P<sub>i</sub>, pH 7.0), simulated fatigue (30 mM P<sub>i</sub>, pH 6.2) and simulated fatigue with dATP conditions. <strong>RESULTS: </strong>Tension declined with high P<sub>i</sub> and H<sup>+</sup> in slow- (type I, 23%) and fast-contracting (type II, 28%) fibers due to fewer strongly bound myosin heads (28-48%) and slower cross-bridge kinetics (longer myosin attachment times (t<sub>on</sub>) (18-40%) and reduced rates of force production (18-30%)). Type I myofilaments became stiffer with high P<sub>i</sub> and H<sup>+</sup> (48%), which may have partially mitigated fatigue-induced tension reduction. Elevated P<sub>i</sub> and H<sup>+</sup> with dATP moderately improved force production similarly in both fiber types (8-11%) compared to high P<sub>i</sub> and H<sup>+</sup> with ATP. In type I fibers, high P<sub>i</sub> and H<sup>+</sup> with dATP returned the number of myosin heads strongly bound and t<sub>on</sub> to normal, while the rate of force production became faster than normal (16%). In type II fibers, high P<sub>i</sub> and H<sup>+</sup> with dATP did not change the number of myosin heads bound, but cross-bridge kinetics were 16-23% faster than normal. <strong>CONCLUSION: </strong>These results identified novel fiber-type specific changes in myosin-actin cross-bridge kinetics and myofilament stiffness that help explain fatigue-related force reduction in human single skeletal muscle fibers as well as an alternative energy source that partially to fully reverses contractile changes of elevated P<sub>i</sub> and H<sup>+</sup> that occur with fatigue.","journal":"ScholarWorks@UMassAmherst (University of Massachusetts Amherst)","year":2021,"id":222725,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9644,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":495237,"name":"Aurora D. Foster","orcid":"0000-0002-2780-8371","position":0,"is_corresponding":true}],"reference_count":108,"raw_metadata":null,"created_at":"2026-07-18T23:54:07.287704Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}