Acetaminophen and Impaired Musculoskeletal Adaptations to Exercise Training

描述（由申请人提供）：机械应力（例如，运动）通过激活环氧合酶（考克斯）而触发骨骼肌和骨中的胡萝卜素（PC）的增加。动物研究中有强有力的证据表明，PG的增加对骨形成至关重要。当考克斯活性被非甾体抗炎药（NSAID）如布洛芬（IBUP）抑制时，骨形成反应几乎完全消失。对乙酰氨基酚（ACET）是一种镇痛药，传统上被认为对考克斯活性只有微弱的抑制作用（如果有的话）。然而，新出现的证据表明，ACET可能确实抑制某些组织中的考克斯活性。如果这发生在肌肉和骨骼中，则这些组织中的机械信号可能会因ACET的使用而受损。解决这一问题的唯一研究发现，IBUP和ACET都减弱了人体骨骼肌对单次抗阻运动的PG增加，并且这伴随着肌肉蛋白质合成分数的减弱增加。还不知道ACET和IBUP响应于单次运动而减弱肌肉PG产生和蛋白质合成的观察到的效果是否在重复运动时持续（即，运动训练），或者ACET和IBUP是否通过类似的机制起作用。ACET是否损害对机械负荷的成骨反应也是未知的。因此，拟议研究的主要目的是确定ACET对运动训练的肌肉骨骼适应性的影响，并评估ACET影响肌肉代谢的潜在机制; IBUP手臂将被纳入以了解ACET和IBUP是否通过类似的机制起作用。年龄60岁以上的男性（n=31）将接受4个月的监督、渐进式运动训练，包括高强度举重和负重运动，以刺激肌肉肥大和骨形成。受试者将被随机分配至ACET（1000 mg/d; n=12）、IBUP（400 mg/d; n=7）或PLAC（n=12）组。假设与PLAC相比，ACET的使用将减弱运动诱导的无脂体重和骨形成标志物的增加。我们进一步假设，与运动+ ACET或+ IBUP相比，运动+ PLAC对AKT/mTOR信号通路的关键组分（例如mTOR、GSK-3）的表达反应不一致。AKT/mTOR通路是骨骼肌蛋白质合成和降解的重要调节剂，并对运动刺激和COX抑制作出反应。这项研究的重要性集中在老年人中广泛使用镇痛药，老年人是肌肉减少症、骨质疏松症和身体损害风险增加的人群。尽管高强度运动有可能改善老年人的肌肉质量、力量、身体功能和骨密度，但使用ACET可能通过干扰机械信号转导来减轻这些肌肉骨骼适应性。

DESCRIPTION (provided by applicant): Mechanical stress (e.g., exercise) triggers an increase in prostaglandins (PCs) in skeletal muscle and bone through activation of the enzyme cyclooxygenase (COX). There is strong evidence from studies of animals that this increase in PGs is essential for bone formation. When COX activity is inhibited by non-steroidal anti- inflammatory drugs (NSAIDs), such as ibuprofen (IBUP), the bone formation response is almost completely abrogated. Acetaminophen (ACET) is an analgesic that has traditionally been thought to have only weak, if any, inhibitory effects on COX activity. However, emerging evidence suggests that ACET may, indeed, inhibit COX activity in some tissues. If this occurs in muscle and bone, it is possible that mechanical signaling in these tissues would be impaired by ACET use. The only study to address this found that both IBUP and ACET blunted the increases in PGs in response to a single bout of resistance exercise in human skeletal muscle, and this was accompanied by a blunted increase in fractional muscle protein synthesis. It is not known whether the observed effects of ACET and IBUP to attenuate muscle PG production and protein synthesis in response to a single bout of exercise persist with repeated bouts of exercise (i.e., exercise training), or whether ACET and IBUP act through similar mechanisms. It is also unknown whether ACET impairs the osteogenic responses to mechanical loading. Thus, the primary aims of the proposed studies are to determine the effects of ACET on the musculoskeletal adaptations to exercise training and to evaluate potential mechanisms by which ACET influence muscle metabolism; an IBUP arm will be included to gain insight into whether ACET and IBUP act through similar mechanisms. Men (n=31), aged 60+ yr, will undergo 4 mo of supervised, progressive exercise training that will include high-intensity weight lifting and weight- bearing exercises to stimulate muscle hypertrophy and bone formation. Participants will be randomized to ACET (1000 mg/d; n=12), IBUP (400 mg/d; n=7), or PLAC (n=12). It is hypothesized that exercise-induced increases in fat-free mass and bone formation markers will be attenuated by the use of ACET compared with PLAC. We further hypothesize that expression of critical components of the AKT/mTOR signaling pathway (e.g. mTOR, GSK-3) will respond discordantly to exercise + PLAC when compared with exercise + ACET or + IBUP. The AKT/mTOR pathway is an important regulator of skeletal muscle protein synthesis and degradation and responds to exercise stimuli and COX-inhibition. The importance of this study centers on the widespread use of analgesics among the elderly, a population at increased risk for sarcopenia, osteoporosis, and physical impairment. Although high-intensity exercise has the potential to improve muscle mass, strength, physical function, and bone mineral density in the elderly, it is possible that the use of ACET mitigates these musculoskeletal adaptations by interfering with mechanical signal transduction.