Debold Edward P, Fitts Robert H, Sundberg Christopher W, Nosek Thomas M
1Department of Kinesiology, University of Massachusetts, Amherst, MA; 2Department of Biological Sciences, Marquette University, Milwaukee, WI; 3Department of Physical Therapy, Marquette University, Milwaukee, WI; and 4Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH.
Med Sci Sports Exerc. 2016 Nov;48(11):2270-2280. doi: 10.1249/MSS.0000000000001047.
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.
骨骼肌反复受到强烈刺激会迅速降低其产生力量和运动的能力。这种类型的疲劳在时间上可能与代谢副产物的积累相关，这些副产物包括磷酸盐（Pi）和质子（H）。对脱膜单根肌纤维的实验表明，这些离子浓度的升高会降低最大等长力、无负荷缩短速度和峰值功率，这为其在疲劳过程中起因果作用提供了有力证据。这似乎部分是由于它们对肌肉分子马达肌球蛋白的直接作用，因为在使用分离蛋白质的实验中，这些离子直接抑制肌球蛋白移动肌动蛋白的能力。事实上，最近使用单分子激光阱实验的研究揭示了这些离子影响横桥循环的具体步骤。除了直接作用外，这些离子还通过降低肌丝对钙的敏感性间接影响肌球蛋白，主要是通过改变肌肉调节蛋白肌钙蛋白和原肌球蛋白控制肌球蛋白与肌动蛋白结合的能力。这种效应似乎部分归因于肌钙蛋白特定亚基结构和功能的疲劳依赖性改变。为理解肌肉收缩分子基础所做的并行努力正在提供新的技术方法，这将使我们能够获得关于疲劳过程前所未有的分子细节。这对于全面理解这种普遍现象以及开发针对性疗法以减轻临床人群中疲劳的衰弱影响至关重要。
