Effects of the Muscle Factor Beta-aminoisobutyric acid, BAIBA, in Old and Young Osteocytes

摘要 显然，运动对身体的许多系统都有有益的影响，如神经、代谢和 肌肉骨骼系统，但目前尚不清楚这些益处是否延缓了衰老的影响，或者衰老是否削弱了这种影响 锻炼身体。骨量减少和骨质疏松症是肌肉骨骼系统老化的主要特征，导致 虚弱、跌倒、骨折和发病。我们已经证明，肌肉和骨骼通过 可溶性因子，特别是肌肉在收缩过程中分泌的影响低分子量的因子 骨头。这些因子保护骨细胞免受糖皮质激素或活性氧诱导的细胞死亡。 物种。这些低分子因子之一是β-氨基异丁酸，简称BAIBA。这种分子有 以前被证明可以诱导白色脂肪的褐变，并改善胰岛素抵抗。我们发现BAIBA 与N-乙酰半胱氨酸和雌激素一样或更有效地防止骨细胞死亡。我们已经开始了 研究BAIBA对过氧化氢保护作用的细胞机制，发现 线粒体在骨细胞中是动态的，BAIBA可以防止它们的分裂和分解。白坝是 由收缩的肌肉产生，鉴于老年和年轻肌肉都产生BAIBA 收缩，BAIBA对22月龄小鼠的老年骨细胞的保护作用不如年轻小鼠 取5月龄小鼠的骨细胞。这表明，不是BAIBA水平在运动中有缺陷 但随着年龄的增长，衰老的骨细胞对BAIBA已不再有反应。BAIBA的一种受体，称为 Mas相关的G蛋白偶联受体D型，MRGPRD在年轻人中表达最高 老年骨细胞减少，这可能是老年骨细胞对BAIBA反应减弱的原因。 BAIBA后肢空载5mo饮水给药的初步体内实验 老年小鼠表明，BAIBA不仅可以保留骨量，还可以保留肌肉功能。我们的假设是：肌肉 作为对运动的反应，会产生BAIBA等因子，保护骨骼以保持骨量。这 BAIBA对骨骼的保护是通过阻断或减少活性氧物种的作用来实现的， ROS，通过维持骨细胞线粒体的动力学及其功能。锻炼 提供BAIBA对骨骼老化的积极作用。为了检验这一假设，具体的目标是 本项目的主要内容是：确定BAIBA用于保护和保存骨骼活力的分子机制 和骨量，并确定BAIBA是否防止骨丢失并调节一些有益的效果 对骨骼和肌肉的锻炼。了解一种低分子分子β-氨基异丁酸， 由肌肉产生，可阻断氧化应激诱导的骨细胞死亡，有可能导致新的 防止骨骼和肌肉因衰老而丢失的治疗方法。因为骨细胞中的线粒体功能是一种新的 在研究领域，我们可能会发现通过维持骨细胞来防止衰老对骨骼的影响的新方法 生存能力和功能。

ABSTRACT Clearly exercise has beneficial effects on many systems in the body such as neural, metabolic and musculoskeletal systems, but it is not clear if these benefits delay the effects of aging or if aging blunts the effects of exercise. Sarcopenia and osteoporosis are major hallmarks of the aging musculoskeletal system resulting in frailty, falls, fracture, and morbidity. We have shown that muscle and bone communicate systemically through soluble factors and specifically that muscle secretes low molecular weight factors during contraction that affect bone. These factors protect osteocytes against cell death induced by either glucocorticoids or by reactive oxygen species. One of these low molecular weight factors is β-aminoisobutyric acid, BAIBA. This molecule has previously been shown to induce the browning of white fat and improve insulin resistance. We found that BAIBA was equal or more potent than n-acetyl cysteine and estrogen to prevent osteocyte cell death. We have begun to examine the cellular mechanisms responsible for the protective effects of BAIBA against H2O2 and found that mitochondria are dynamic in osteocytes and that BAIBA prevents their fission and breakdown. BAIBA is produced by contracted muscle, and whereas both old and young muscle produce BAIBA in response to contraction, old osteocytes from 22 month old mice are not protected by BAIBA to the same extent as young osteocytes from 5 month old mice. This suggests that it is not the levels of BAIBA that are defective with exercise with aging but that aged osteocytes can no longer respond to BAIBA. One receptor for BAIBA, known as the mas-related G-protein coupled receptor, type D, MRGPRD, was found to be most highly expressed in young osteocytes, but decreased in old osteocytes which may be why old osteocytes have reduced response to BAIBA. Our preliminary in vivo experiments where BAIBA is administered in drinking water to hindlimb unloaded 5 mo old mice suggests that BAIBA can retain not only bone mass but also muscle function. Our hypothesis is: Muscle in response to exercise produces factors such as BAIBA, that protect bone to maintain bone mass. This protection of bone by BAIBA is achieved by blocking or reducing the effects of reactive oxygen species, ROS, through the maintenance of osteocyte mitochondrial dynamics and their function. Exercise provides the positive effects of BAIBA on the skeleton with aging. To test this hypothesis, the specific aims of this project are: To determine the molecular mechanism used by BAIBA to protect and preserve bone viability and bone mass and to determine if BAIBA protects against bone loss and mediates some of the beneficial effects of exercise on bone and on muscle. Understanding how a low molecular molecule, β-aminoisobutyric acid, produced by muscle, can block oxidative stress induced osteocyte cell death has the potential to lead to new therapeutics to prevent both bone and muscle loss with aging. As mitochondrial function in osteocytes is a new area of research, we may discover new means to prevent the effects of aging on bone by maintaining osteocyte viability and function.