Fatigability of Limb Muscle in Older Adults: Protective Effects of Exercise

摘要 肢体肌肉质量的损失和疲劳性的增加损害了老年人（≥65岁）的能力， 产生维持移动性和进行日常活动所需的电力。最近，我们发现， 在动态收缩期间与年龄相关的易疲劳性增加是由于代谢物的更大积累， 氢（H+），无机磷酸盐（Pi）和二质子化磷酸盐（H2 PO 4-），引起更大的破坏， 肌肉内的收缩功能。然而，代谢物蓄积更大的机制是 未知我们的中心假设是，代谢物的大量积累和疲劳性的增加， 这是由于骨骼肌生物能量学和/或血管功能中与年龄相关的损伤。为了验证这个假设， 我们将使用尖端技术来评估整个肌肉和单纤维生物能量学和宏观， 微血管功能此外，我们将研究一种新的运动训练干预的有效性， 老年男性和女性旨在改善收缩经济性、血管功能、肌肉力量和疲劳性。 目的1将确定与年龄相关的整个股四头肌疲劳性增加的生物能量学基础 肌肉和从股外侧肌的肌肉活检分离的单纤维。四头肌收缩 经济性和细胞内代谢产物（H+，Pi，H2 PO 4-）的积累将与31磷进行评估 动态伸膝运动中的核磁共振波谱（31 P-MRS）。肌原纤维和 肌浆网-Ca 2 + ATP酶活性和纤维效率也将在缩短过程中测量 使用落射荧光显微镜观察单纤维的收缩。我们假设老年人会有一个 全肌和单纤维收缩经济性低于青年人。目标2将评估是否 大脉管系统和微脉管系统的功能障碍是随年龄增长而增加的疲劳性的机制。期间 动态膝关节伸展运动，股动脉血流将通过多普勒超声进行量化， 用近红外光谱（NIRS）测量组织氧合。将评估微血管功能 在从股外侧肌活检分离的小动脉中使用视频显微镜。我们假设老年人 股动脉血流量减少，股四头肌氧合减少更大， 年轻人，部分原因是由于小动脉的血管反应性减弱。目标3将决定 高速抗阻运动训练结合血流限制改善老年男性疲劳 和妇女老年人将进行8周的动态单侧阻力运动，其中一条腿是 在自由灌注条件下运动，另一个在血流限制条件下运动。我们假设 在运动训练中，血流量受限的腿的疲劳性、生物能量学和血管功能将得到改善 这些改善将比单纯的运动训练更大。该提案将深入了解 与年龄相关的疲劳机制，并转化为临床相关的运动计划的发展 最大限度地提高老年男性和女性的训练适应能力，以改善流动性和生活质量。

ABSTRACT Losses in limb muscle mass and increased fatigability compromise the ability of older adults (≥65 yrs) to generate the power necessary to maintain mobility and perform daily activities. Recently, we showed that the age-related increase in fatigability during dynamic contractions is due to a greater accumulation of metabolites, hydrogen (H+), inorganic phosphate (Pi) and diprotonated phosphate (H2PO4-), eliciting greater disruptions in contractile function within the muscle. However, the mechanisms for the greater metabolite accumulation are unknown. Our central hypothesis is that the greater accumulation of metabolites and increased fatigability are due to age-related impairments in skeletal muscle bioenergetics and/or vascular function. To test this hypothesis, we will use cutting-edge techniques to assess whole-muscle and single fiber bioenergetics and macro- and micro-vascular function. Additionally, we will study the effectiveness of a novel exercise-training intervention in older men and women aimed at improving contractile economy, vascular function, muscle power and fatigability. Aim 1 will determine the bioenergetic basis for the age-related increase in fatigability in the whole quadriceps muscle and in single fibers isolated from muscle biopsies of the vastus lateralis. Quadriceps muscle contractile economy and the accumulation of intracellular metabolites (H+, Pi, H2PO4-) will be assessed with 31phosphorus nuclear magnetic resonance spectroscopy (31P-MRS) during dynamic knee extension exercise. Myofibrillar and sarcoplasmic reticulum-Ca2+ ATPase activity and fiber efficiency will also be measured during shortening contractions of single fibers using epifluorescence microscopy. We hypothesize that older adults will have a lower whole muscle and single fiber contractile economy compared with young adults. Aim 2 will assess whether dysfunction of the macro- and micro-vasculature is a mechanism for the increased fatigability with aging. During dynamic knee extension exercise, femoral artery blood flow will be quantified via Doppler ultrasonography and tissue oxygenation measured with near infrared spectroscopy (NIRS). Microvascular function will be assessed in arterioles isolated from vastus lateralis biopsies using video microscopy. We hypothesize that older adults will have reduced femoral artery blood flow and greater reductions in quadriceps muscle oxygenation compared with young adults, in part, due to a blunted vasoreactivity of arterioles. Aim 3 will determine the effectiveness of a high-velocity resistance exercise training coupled with blood flow restriction to improve fatigability in older men and women. Older adults will perform 8 weeks of dynamic unilateral resistance exercise, where one leg is exercised with freely perfused conditions and the other with blood flow restriction. We hypothesize that fatigability, bioenergetics and vascular function will improve in the exercise training leg with blood flow restriction and these improvements will be greater than exercise-training alone. This proposal will provide insight into the mechanisms of age-related fatigability and translate into the development of clinically relevant exercise programs that maximize the training adaptations in older men and women to improve mobility and quality of life.