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Using sinusoidal analysis, the independent and combined effects of these metabolites on cellular and molecular contractile function were determined at 37\u00b0C in slow-contracting myosin heavy chain (MHC) I and fast-contracting MHC IIA fibers from vastus lateralis muscle of 13 older adults (8 females), under four conditions: maximal calcium activation (\u201ccontrol\u201d; 5 mM P\n                  <jats:sub>i<\/jats:sub>\n                  , pH 7.0), high P\n                  <jats:sub>i<\/jats:sub>\n                  (30 mM), low pH (6.2), and fatigue (30 mM P\n                  <jats:sub>i<\/jats:sub>\n                  and pH 6.2). Specific tension (force\/cross-sectional area, mN\/mm\n                  <jats:sup>2<\/jats:sup>\n                  ) in both fiber types was reduced only under fatigue conditions (20-26%). MHC I fibers had slower cross-bridge kinetics with fewer or less stiff strongly-bound myosin-actin cross-bridges in high P\n                  <jats:sub>i<\/jats:sub>\n                  , low pH, and fatigue. In contrast, fatigued MHC IIA fibers had faster cross-bridge kinetics with increased myofilament and\/or cross-bridge viscosity. Single fiber oscillatory work was reduced in both fiber types when P\n                  <jats:sub>i<\/jats:sub>\n                  or pH alone was altered. However, fatigue conditions returned oscillatory work values toward control through alterations to cross-bridge kinetics in MHC I fibers and changes to work absorption and production processes in MHC IIA fibers. These findings quantify fiber-type specific mechanical and kinetic mechanisms of fatigue in human skeletal muscle at 37\u00b0C, thus advancing our understanding of metabolite-based muscle fatigue\n                  <jats:italic>in vivo<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>KEY POINTS SUMMARY<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Working skeletal muscle increases intracellular concentrations of hydrogen ion and inorganic phosphate, leading to fatigue, or loss of force-generating capacity<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Temperature plays a well-established role in the muscle response to hydrogen ion and\/or inorganic phosphate accumulation, but has not previously been studied at human body temperature (37\u00b0C)<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>At 37\u00b0C, reduced force generation only occurs when high phosphate and hydrogen ions are combined, not when changed individually<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>In slow-contracting fibers, fatigue slowed myosin-actin cross-bridge kinetics and reduced the number or stiffness of strongly-bound cross-bridges. In fast-contracting fibers, fatigue increased myosin-actin cross-bridge kinetics and increased myofilament viscosity.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The distinct responses by fiber type to fatigue provides new insight into its mechanisms and advances our understanding of the whole muscle and body responses to fatigue<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Abstract Figure<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"672942v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                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