Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial

Unacylated Ghrelin改善PAD的功能：GIFT试验 我们和其他人的工作表明，下肢外周动脉疾病(PAD)患者 功能损害更大，功能衰退更快，移动性损失率更高 没有PAD的人。在PAD患者中，缺血导致小腿肌肉损伤，包括肌纤维丢失。 和小腿肌肉线粒体功能障碍。再生小牛骨骼肌细胞的治疗方法，改善 线粒体功能和增加小腿肌肉毛细血管密度可能会改善功能和防止活动 在患有PAD的人中丢失。然而，目前几乎没有有效的治疗方法来治疗PAD患者。 这项先导性研究将探讨未酰化生长激素促进毛细血管生长的治疗潜力。 生长，增加小腿肌肉的灌注量，逆转与PAD相关的骨骼肌异常，从而 改善与PAD相关的功能损害。Ghrelin是一种多肽和激素，在酰化和 非酰化形式。非酰化Ghrelin促进骨骼肌细胞再生，改善线粒体 功能，增加肌肉毛细血管密度。与酰化的Ghrelin不同，未酰化的Ghrelin不会增加 食欲，或引起胰岛素抵抗。 拟议的GIFT试验将提供初步数据来验证我们的假设 改善老年PAD患者的行走能力，防止行动不便。我们进一步假设 未酰化的Ghrelin的有利作用将通过增加肌纤维再生而介导 增加肌肉毛细血管密度，改善肌肉线粒体功能。如果我们的初步数据支持我们的 假设，结果将被用来设计一项大规模的随机试验，在随后的治疗中 研究，以改善患有PAD的老年人的功能和预防行动不便。 我们将在30名60岁及以上的PAD参与者中进行试点随机试验，以收集 关于每天皮下给药是否能改善6分钟时间的初步证据 步行距离(主要结果)、最大跑步机步行距离(次要结果)和小腿肌肉 与安慰剂相比，灌注(次要结果)。我们还将在基线上进行小腿肌肉活组织检查 并随访以确定未酰化生长激素是否增加1型骨骼肌肌纤维，卫星 小牛骨骼中细胞数、毛细血管密度和琥珀酸脱氢酶(SDH)线粒体活性 肌肉，与安慰剂相比。如果我们的假设是正确的，结果将被用来设计一个大型的、明确的 非酰化Ghrelin改善患者肢体功能和预防运动能力丧失的随机试验 被PAD致残的老年人数量庞大，而且还在不断增加。

Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial Our work and that of others shows that patients with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and higher rates of mobility loss compared to people without PAD. In patients with PAD, ischemia results in calf muscle injury that includes myofiber loss and calf muscle mitochondrial dysfunction. Therapies to regenerate calf skeletal muscle cells, improve mitochondrial function, and increase calf muscle capillary density may improve functioning and prevent mobility loss in people with PAD. Yet few effective therapies currently exist for patients with PAD. This pilot study will investigate the therapeutic potential of unacylated ghrelin to promote capillary growth, increase calf muscle perfusion, and reverse PAD-related skeletal muscle abnormalities, thereby improving PAD-related functional impairment. Ghrelin is a peptide and hormone that circulates in acylated and unacylated forms. Unacylated ghrelin promotes skeletal muscle cell regeneration, improves mitochondrial function, and increases muscle capillary density. Unlike acylated ghrelin, unacylated ghrelin does not increase appetite, or cause insulin resistance. The proposed GIFT Trial will provide preliminary data to test our hypothesis that unacylated ghrelin improves walking performance and prevents mobility loss in older patients with PAD. We further hypothesize that the favorable effect of unacylated ghrelin will be mediated by increased myofiber regeneration, increased muscle capillary density, and improved muscle mitochondria function. If our preliminary data support our hypotheses, results will be used to design a large randomized trial of unacylated ghrelin therapy, in subsequent study, to improve functioning and prevent mobility loss in older people with PAD. We will conduct a pilot randomized trial in 30 participants age 60 and older with PAD, to gather preliminary evidence about whether daily subcutaneously administered unacylated improves the six-minute walk distance (primary outcome), maximal treadmill walking distance (secondary outcome), and calf muscle perfusion (secondary outcome), compared to placebo. We will also perform calf muscle biopsies at baseline and follow up to determine whether unacylated ghrelin increases Type 1 skeletal muscle myofibers, satellite cell number, capillary density, and succinate dehydrogenase (SDH) mitochondrial activity in calf skeletal muscle, compared to placebo. If our hypotheses are correct, results will be used to design a large, definitive randomized trial of unacylated ghrelin to improve lower extremity functioning and prevent mobility loss in the large and growing number of older people who are disabled by PAD.