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Key Points: The mechanisms responsible for the loss in muscle power and increased fatigability with ageing are unresolved. We show that the contractile mechanics of fibres from the vastus lateralis of old men were well-preserved compared to those of young men, but the selective loss of fast myosin heavy chain II muscle was strongly associated with age-related decrements in whole-muscle strength and power. We reveal that the combination of acidosis (H + ) and inorganic phosphate (P i ) is an important mediator of muscle fatigue in humans by inhibiting the low- to high-force state of the cross-bridge cycle and peak power, but the depressive effects of these ions on cross-bridge function were similar in fibres from young and old men. These findings suggest that the age-related loss in muscle power is primarily determined by the atrophy of fast fibres, but the age-related increased fatigability cannot be explained by an increased sensitivity of the cross-bridge to H + and P i ., Abstract: The present study aimed to identify the mechanisms responsible for the loss in muscle power and increased fatigability with ageing by integrating measures of whole-muscle function with single fibre contractile mechanics. After adjusting for the 22% smaller muscle mass in old (73-89 years, n = 6) compared to young men (20-29 years, n = 6), isometric torque and power output of the knee extensors were, respectively, 38% and 53% lower with age. Fatigability was ∼2.7-fold greater with age and strongly associated with reductions in the electrically-evoked contractile properties. To test whether cross-bridge mechanisms could explain age-related decrements in knee extensor function, we exposed myofibres (n = 254) from the vastus lateralis to conditions mimicking quiescent muscle and fatiguing levels of acidosis (H + ) (pH 6.2) and inorganic phosphate (P i ) (30 mm). The fatigue-mimicking condition caused marked reductions in force, shortening velocity and power and inhibited the low- to high-force state of the cross-bridge cycle, confirming findings from non-human studies that these ions act synergistically to impair cross-bridge function. Other than severe age-related atrophy of fast fibres (-55%), contractile function and the depressive effects of the fatigue-mimicking condition did not differ in fibres from young and old men. The selective loss of fast myosin heavy chain II muscle was strongly associated with the age-related decrease in isometric torque (r = 0.785) and power (r = 0.861). These data suggest that the age-related loss in muscle strength and power are primarily determined by the atrophy of fast fibres, but the age-related increased fatigability cannot be explained by an increased sensitivity of the cross-bridge to H + and P i ., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

The repeated intense stimulation of skeletal muscle rapidly decreases its force- and motion-generating capacity. This type of fatigue can be temporally correlated with the accumulation of metabolic by-products, including phosphate (Pi) and protons (H). Experiments on skinned single muscle fibers demonstrate that elevated concentrations of these ions can reduce maximal isometric force, unloaded shortening velocity, and peak power, providing strong evidence for a causative role in the fatigue process. This seems to be due, in part, to their direct effect on muscle's molecular motor, myosin, because in assays using isolated proteins, these ions directly inhibit myosin's ability to move actin. Indeed, recent work using a single molecule laser trap assay has revealed the specific steps in the crossbridge cycle affected by these ions. In addition to their direct effects, these ions also indirectly affect myosin by decreasing the sensitivity of the myofilaments to calcium, primarily by altering the ability of the muscle regulatory proteins, troponin and tropomyosin, to govern myosin binding to actin. This effect seems to be partially due to fatigue-dependent alterations in the structure and function of specific subunits of troponin. Parallel efforts to understand the molecular basis of muscle contraction are providing new technological approaches that will allow us to gain unprecedented molecular detail of the fatigue process. This will be crucial to fully understand this ubiquitous phenomenon and develop appropriately targeted therapies to attenuate the debilitating effects of fatigue in clinical populations.

Skeletal muscle fatigue is characterized by the buildup of H(+) and inorganic phosphate (Pi), metabolites that are thought to cause fatigue by inhibiting muscle force, velocity, and power. While the individual effects of elevated H(+) or Pi have been well characterized, the effects of simultaneously elevating the ions, as occurs during fatigue in vivo, are still poorly understood. To address this, we exposed slow and fast rat skinned muscle fibers to fatiguing levels of H(+) (pH 6.2) and Pi (30 mM) and determined the effects on contractile properties. At 30°C, elevated Pi and low pH depressed maximal shortening velocity (Vmax) by 15% (4.23 to 3.58 fl/s) in slow and 31% (6.24 vs. 4.55 fl/s) in fast fibers, values similar to depressions from low pH alone. Maximal isometric force dropped by 36% in slow (148 to 94 kN/m(2)) and 46% in fast fibers (148 to 80 kN/m(2)), declines substantially larger than what either ion exerted individually. The strong effect on force combined with the significant effect on velocity caused peak power to decline by over 60% in both fiber types. Force-stiffness ratios significantly decreased with pH 6.2 + 30 mM Pi in both fiber types, suggesting these ions reduced force by decreasing the force per bridge and/or increasing the number of low-force bridges. The data indicate the collective effects of elevating H(+) and Pi on maximal isometric force and peak power are stronger than what either ion exerts individually and suggest the ions act synergistically to reduce muscle function during fatigue., (Copyright © 2014 the American Physiological Society.)

Skeletal muscle fatigue is defined as the fall of force or power in response to contractile activity. Both the mechanisms of fatigue and the modes used to elicit it vary tremendously. Conceptual and technological advances allow the examination of fatigue from the level of the single molecule to the intact organism. Evaluation of muscle fatigue in a wide range of disease states builds on our understanding of basic function by revealing the sources of dysfunction in response to disease., (© 2012 American Physiological Society. Compr Physiol 2:997-1044, 2012.)

The functional correlates of fatigue observed in both animals and humans during exercise include a decline in peak force (P0), maximal velocity, and peak power. Establishing the extent to which these deleterious functional changes result from direct effects on the myofilaments is facilitated through understanding the molecular mechanisms of the cross-bridge cycle. With actin-myosin binding, the cross-bridge transitions from a weakly bound low-force state to a strongly bound high-force state. Low pH reduces the number of high-force cross bridges in fast fibers, and the force per cross bridge in both fast and slow fibers. The former is thought to involve a direct inhibition of the forward rate constant for transition to the strong cross-bridge state. In contrast, inorganic phosphate (Pi) is thought to reduce P0 by accelerating the reversal of this step. Both H+ and Pi decrease myofibrillar Ca2+ sensitivity. This effect is particularly important as the amplitude of the Ca2+ transient falls with fatigue. The inhibitory effects of low pH and high Pi on P0 are reduced as temperature increases from 10 to 30 degrees C. However, the H+-induced depression of peak power in the slow fiber type, and Pi inhibition of myofibrillar Ca2+ sensitivity in slow and fast fibers, are greater at high compared with low temperature. Thus the depressive effects of H+ and Pi at in vivo temperatures cannot easily be predicted from data collected below 25 degrees C. In vitro, reactive oxygen species reduce myofibrillar Ca2+ sensitivity; however, the importance of this mechanism during in vivo exercise is unknown.

Key points: The mechanisms for the age‐related increase in fatigability during dynamic exercise remain elusive.We tested whether age‐related impairments in muscle oxidative capacity would result in a greater accumulation of fatigue causing metabolites, inorganic phosphate (Pi), hydrogen (H+) and diprotonated phosphate (H2PO4−), in the muscle of old compared to young adults during a dynamic knee extension exercise.The age‐related increase in fatigability (reduction in mechanical power) of the knee extensors was closely associated with a greater accumulation of metabolites within the working muscle but could not be explained by age‐related differences in muscle oxidative capacity.These data suggest that the increased fatigability in old adults during dynamic exercise is primarily determined by age‐related impairments in skeletal muscle bioenergetics that result in a greater accumulation of metabolites. The present study aimed to determine whether the increased fatigability in old adults during dynamic exercise is associated with age‐related differences in skeletal muscle bioenergetics. Phosphorus nuclear magnetic resonance spectroscopy was used to quantify concentrations of high‐energy phosphates and pH in the knee extensors of seven young (22.7 ± 1.2 years; six women) and eight old adults (76.4 ± 6.0 years; seven women). Muscle oxidative capacity was measured from the phosphocreatine (PCr) recovery kinetics following a 24 s maximal voluntary isometric contraction. The fatiguing exercise consisted of 120 maximal velocity contractions (one contraction per 2 s) against a load equivalent to 20% of the maximal voluntary isometric contraction. The PCr recovery kinetics did not differ between young and old adults (0.023 ± 0.007 s−1 vs. 0.019 ± 0.004 s−1, respectively). Fatigability (reductions in mechanical power) of the knee extensors was ∼1.8‐fold greater with age and was accompanied by a greater decrease in pH (young = 6.73 ± 0.09, old = 6.61 ± 0.04) and increases in concentrations of inorganic phosphate, [Pi], (young = 22.7 ± 4.8 mm, old = 32.3 ± 3.6 mm) and diprotonated phosphate, [H2PO4−], (young = 11.7 ± 3.6 mm, old = 18.6 ± 2.1 mm) at the end of the exercise in old compared to young adults. The age‐related increase in power loss during the fatiguing exercise was strongly associated with intracellular pH (r = –0.837), [Pi] (r = 0.917) and [H2PO4−] (r = 0.930) at the end of the exercise. These data suggest that the age‐related increase in fatigability during dynamic exercise has a bioenergetic basis and is explained by an increased accumulation of metabolites within the muscle. Key points: The mechanisms for the age‐related increase in fatigability during dynamic exercise remain elusive.We tested whether age‐related impairments in muscle oxidative capacity would result in a greater accumulation of fatigue causing metabolites, inorganic phosphate (Pi), hydrogen (H+) and diprotonated phosphate (H2PO4−), in the muscle of old compared to young adults during a dynamic knee extension exercise.The age‐related increase in fatigability (reduction in mechanical power) of the knee extensors was closely associated with a greater accumulation of metabolites within the working muscle but could not be explained by age‐related differences in muscle oxidative capacity.These data suggest that the increased fatigability in old adults during dynamic exercise is primarily determined by age‐related impairments in skeletal muscle bioenergetics that result in a greater accumulation of metabolites. [ABSTRACT FROM AUTHOR]

Key points: The mechanisms responsible for the loss in muscle power and increased fatigability with ageing are unresolved. We show that the contractile mechanics of fibres from the vastus lateralis of old men were well‐preserved compared to those of young men, but the selective loss of fast myosin heavy chain II muscle was strongly associated with age‐related decrements in whole‐muscle strength and power. We reveal that the combination of acidosis (H+) and inorganic phosphate (Pi) is an important mediator of muscle fatigue in humans by inhibiting the low‐ to high‐force state of the cross‐bridge cycle and peak power, but the depressive effects of these ions on cross‐bridge function were similar in fibres from young and old men. These findings suggest that the age‐related loss in muscle power is primarily determined by the atrophy of fast fibres, but the age‐related increased fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi. Abstract: The present study aimed to identify the mechanisms responsible for the loss in muscle power and increased fatigability with ageing by integrating measures of whole‐muscle function with single fibre contractile mechanics. After adjusting for the 22% smaller muscle mass in old (73–89 years, n = 6) compared to young men (20–29 years, n = 6), isometric torque and power output of the knee extensors were, respectively, 38% and 53% lower with age. Fatigability was ∼2.7‐fold greater with age and strongly associated with reductions in the electrically‐evoked contractile properties. To test whether cross‐bridge mechanisms could explain age‐related decrements in knee extensor function, we exposed myofibres (n = 254) from the vastus lateralis to conditions mimicking quiescent muscle and fatiguing levels of acidosis (H+) (pH 6.2) and inorganic phosphate (Pi) (30 m m). The fatigue‐mimicking condition caused marked reductions in force, shortening velocity and power and inhibited the low‐ to high‐force state of the cross‐bridge cycle, confirming findings from non‐human studies that these ions act synergistically to impair cross‐bridge function. Other than severe age‐related atrophy of fast fibres (−55%), contractile function and the depressive effects of the fatigue‐mimicking condition did not differ in fibres from young and old men. The selective loss of fast myosin heavy chain II muscle was strongly associated with the age‐related decrease in isometric torque (r = 0.785) and power (r = 0.861). These data suggest that the age‐related loss in muscle strength and power are primarily determined by the atrophy of fast fibres, but the age‐related increased fatigability cannot be explained by an increased sensitivity of the cross‐bridge to H+ and Pi. [ABSTRACT FROM AUTHOR]

Intense muscle contraction induces high rates of ATP hydrolysis with resulting increases in Pi, H+, and ADP, factors thought to induce fatigue by interfering with steps in the cross-bridge cycle. Force inhibition is less at physiological temperatures; thus the role of low pH in fatigue has been questioned. Effects of pH 6.2 and collective effects with 30 mM Pi on the pCa-force relationship were assessed in skinned fast and slow rat skeletal muscle fibers at 15 and 30°C. At 30°C, pH 6.2 + 30 mM Pi significantly depressed peak force in all fiber types, with the greatest effect in type IIx fibers. Across fiber types, Ca2+ sensitivity was depressed by low pH and low pH + high Pi, with the greater effect at 30°C. For type IIx fibers at 30°C, half-maximal activation (pCa50) was 5.36 at pH 6.2 (no added Pi) and 4.98 at pH 6.2 + 30 mM Pi compared with 6.58 in the control condition (pH 7, no added Pi). At 30°C, n2, reflective of thick filament cooperativity, was unchanged by low cell pH but was depressed from 5.02 to 2.46 in type IIx fibers with pH 6.2 + 30 mM Pi. With acidosis, activation thresholds of all fiber types required higher free Ca(2+) at 15 and 30°C. With the exception of type IIx fibers, the Ca2+ required to reach activation threshold increased further with added Pi. In conclusion, it is clear that fatigue-inducing effects of low cell pH and elevated Pi at near-physiological temperatures are substantial. [ABSTRACT FROM AUTHOR]