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

摘要 显然，锻炼对身体的许多系统都有有益的影响，如神经系统、代谢系统和神经系统。 肌肉骨骼系统，但目前尚不清楚这些好处是否会延迟衰老的影响，或者是否会减弱衰老的影响 锻炼。肌肉减少症和骨质疏松症是肌肉骨骼系统老化的主要标志， 虚弱、福尔斯、骨折和发病率。我们已经证明，肌肉和骨骼系统地沟通，通过 可溶性因子，特别是肌肉在收缩过程中分泌低分子量因子， 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 物种这些低分子量因子之一是β-氨基异丁酸，BAIBA。这种分子具有 先前已显示诱导白色脂肪的布朗宁并改善胰岛素抗性。我们发现， 与N-乙酰半胱氨酸和雌激素相比，其预防骨细胞死亡的效力相等或更强。我们已经开始 为了检查负责BAIBA对H2 O2的保护作用的细胞机制，发现 线粒体在骨细胞中是动态的，BAIBA防止其分裂和分解。BAIBA是 由收缩的肌肉产生，而老年人和年轻人的肌肉都产生BAIBA， 收缩，来自22月龄小鼠的老年骨细胞不受BAIBA保护到与年轻相同的程度 来自5个月大的小鼠的骨细胞。这表明，这不是BAIBA的水平与运动有缺陷 随着年龄的增长，但老化的骨细胞不再对BAIBA产生反应。BAIBA的一种受体，称为 mas相关的G蛋白偶联受体，D型，MRGPRD，被发现在年轻人中表达最高。 骨细胞对BAIBA的反应性降低，而老年骨细胞对BAIBA的反应性降低，这可能是老年骨细胞对BAIBA反应性降低的原因。 我们的初步体内实验中，白巴在饮用水中给药到后肢卸载5个月 提示白扒不仅能保持骨量，还能保持肌肉功能。我们的假设是：肌肉 在应对运动产生的因素，如BAIBA，保护骨骼，保持骨量。这 BAIBA对骨的保护是通过阻断或减少活性氧的作用来实现的， ROS，通过维持骨细胞线粒体的动力学而发挥作用。行使 提供了白芭对骨骼衰老的积极作用。为了验证这一假设， 本项目的主要内容是：确定BAIBA保护和保存骨活力的分子机制 和骨量，并确定白巴是否能防止骨质流失，并介导一些有益的作用， 对骨骼和肌肉的影响。了解低分子量的β-氨基异丁酸， 由肌肉产生，可以阻断氧化应激诱导的骨细胞死亡，有可能导致新的 治疗，以防止骨骼和肌肉的损失与老化。由于骨细胞中的线粒体功能是一个新的 在这一研究领域，我们可能会发现通过维持骨细胞来防止衰老对骨的影响的新方法。 可行性和功能。

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.