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 提供维持机动性和进行日常活动所需的电力。最近，我们展示了 在动态收缩期间与年龄相关的疲劳性增加是由于代谢物的更大积累， 氢(H+)、无机磷(PI)和二质子化磷酸(H2PO4-)，引起更大的干扰 肌肉内的收缩功能。然而，代谢产物积累较大的机制是 未知。我们的中心假设是，代谢产物的积累越多，疲劳性越强 由于骨骼肌生物能量学和/或血管功能的年龄相关损害。为了检验这一假设， 我们将使用尖端技术评估全肌肉和单纤维生物能量学和宏观和 微血管功能。此外，我们还将研究一种新的运动训练干预措施在 老年男性和女性旨在改善收缩经济、血管功能、肌肉力量和疲劳性。 目标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基础 肌肉和股外侧肌活组织中分离出的单个纤维。股四头肌收缩 经济性和细胞内代谢物(H+、PI、H2PO4-)的积累将用31P进行评估 动态伸膝运动核磁共振波谱(31P-MRS)研究。肌原纤维和 在缩短过程中还将测量肌浆网-钙-ATPase活性和纤维效率 用荧光显微镜观察单个纤维的收缩。我们假设老年人会有一个 与青壮年相比，整体肌肉和单纤维收缩经济性较低。目标2将评估是否 大血管和微血管系统功能障碍是随着年龄增长疲劳性增加的一个机制。在.期间 动态伸膝运动，股动脉血流量将通过多普勒超声和 用近红外光谱仪(NIRS)测量组织氧合。将评估微血管功能 在视频显微镜下从股外侧肌活检中分离出的小动脉。我们假设老年人会 减少了股动脉的血流量，股四头肌的氧合比 年轻人，部分原因是小动脉血管反应迟钝。目标3将决定一项 高速耐力运动训练结合血流限制改善老年男性的疲劳性 还有女人。老年人将进行为期8周的动态单侧阻力练习，其中一条腿是 一组在自由灌流条件下运动，另一组在血流受限的情况下运动。我们假设 血流受限运动训练腿的疲劳性、生物能量学和血管功能改善 这些改善将比单纯的运动训练更大。这份提案将为我们提供对 与年龄相关的疲劳性的机制并转化为临床相关运动计划的发展 这将最大限度地提高老年男子和妇女的训练适应能力，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.