THE LEPTIN-IGF1 AXIS IN MUSCULOSKELETAL AGING

衰老与体重减轻有关，通常被称为衰老厌食症，伴随而来的是肌肉质量的丧失(骨质疏松症)和骨骼丢失(骨质疏松)。瘦素是一种细胞因子样激素，由脂肪和骨骼肌等外周脂肪分泌，瘦素缺乏与骨量减少、肌肉质量和力量丧失有关。我们已经确定了一个动物模型，老年C57BL/6小鼠，它与衰老的人类肌肉骨骼系统有许多共同的关键特征：与年龄相关的血清瘦素下降，血清IGF-1下降，肌肉质量下降，骨密度下降。我们还发现，瘦素治疗增加了老年小鼠的血清IGF-1和肌肉质量。因此，我们的初步研究表明，随着年龄的增长，肌肉骨骼功能的下降部分是由于瘦素-IGFI轴的改变。我们还首次显示，来自老龄小鼠的肌肉骨骼组织显示出增强的 针对瘦素的microRNAs(MiRNAs)。我们建议的中心假设是瘦素是连接营养摄入和正常肌肉骨骼功能的关键因素，但肌肉骨骼组织中的瘦素信号随着年龄的增长而改变，直接导致与年龄相关的肌肉和骨骼的丧失。具体目标1将确定瘦素表达随年龄变化的细胞和组织特异性变化，并将确定循环瘦素在调节与年龄相关的局部和全身IGF-1分泌变化中的作用。目的2将确定衰老和营养摄入如何改变瘦素敏感性和肌肉和骨细胞中功能性瘦素受体的表达。目的3将识别随着年龄和瘦素治疗而改变的FISE特异性microRNAs，并将利用体外功能研究来确定这些小分子在肌源性细胞和成骨细胞增殖和分化中的作用。因此，拟议的研究将确定与骨质疏松症和跌倒风险相关的新的治疗靶点和诊断生物标记物，可以开发这些标记物来改进现有的骨折治疗和预防策略。

Aging is associated with a loss of body weight, often referred to as the anorexia of aging, which is accompanied by loss of muscle mass (sarcopenia) and bone loss (osteoporosis). The cytokine-like hormone leptin is secreted from peripheral fissues including fat and skeletal muscle, and leptin deficiency is associated with decreased bone mass as well as loss of muscle mass and strength. We have identified an animal model, the aged C57BL/6 mouse, that shares a number of key features in common with the aging human musculoskeletal system: an age-related decline in serum lepfin, decline in serum IGF-1, decreased muscle mass, and loss of bone density. We have also found that leptin treatment increases serum IGF-1 and muscle mass in aged mice. Our preliminary studies therefore suggest that the decline in musculoskeletal funcfion that occurs with aging is due in part to alterations in the lepfin-IGFI axis. We also show for the first time that musculoskeletal tissues from aged mice show increased expression of microRNAs (miRNAs) targefing leptin. The central hypothesis of our proposal is that leptin is a key factor linking nutrient intake with normal musculoskeletal funcfion, but leptin signaling in musculoskeletal tissues is altered with age, contributing direcfiy to age-related loss of muscle and bone. Specific Aim 1 will identify cell- and tissue-specific alterations in leptin expression with age, and will define the role of circulating leptin in regulating age-associated changes in the local and systemic secretion of IGF-1. Aim 2 will determine how aging and nutrient intake alter leptin sensitivity and the expression of functional leptin receptors in muscle and bone cells. Aim 3 will identify fissue-specific microRNAs that are altered with age and leptin treatment, and functional in vitro studies will be used to define the role of these small molecules in the proliferation and differentiation of myogenic and osteogenic cells. The proposed studies will therefore define new therapeutic targets and diagnostic biomarkers related to sarcopenia and fall risk that can be developed to improve upon exisfing fracture treatment and prevention strategies.