THE LEPTIN-IGF1 AXIS IN MUSCULOSKELETAL AGING

衰老与体重减轻有关，通常被称为衰老的厌食症，其伴随着肌肉质量的损失（肌肉减少症）和骨质流失（骨质疏松症）。瘦素样激素瘦素是从包括脂肪和骨骼肌在内的外周脂肪组织分泌的，瘦素缺乏与骨量减少以及肌肉质量和力量损失有关。我们已经确定了一种动物模型，老年C57 BL/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：血清瘦素的年龄相关性下降，血清IGF-1下降，肌肉质量下降和骨密度损失。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。我们还首次发现，来自老年小鼠的肌肉骨骼组织中， 靶向瘦素的microRNAs（miRNAs）。我们提出的中心假设是瘦素是连接营养摄入与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变化而改变，直接导致与年龄相关的肌肉和骨骼损失。具体目标1将确定瘦素表达随年龄的细胞和组织特异性变化，并将确定循环瘦素在调节局部和全身IGF-1分泌的年龄相关变化中的作用。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。目标3将确定随年龄和瘦素治疗而改变的裂隙特异性microRNA，并将使用功能性体外研究来确定这些小分子在肌原性和成骨细胞增殖和分化中的作用。因此，拟议的研究将定义与肌肉减少症和跌倒风险相关的新的治疗靶点和诊断生物标志物，可以开发这些靶点和诊断生物标志物来改善骨折的治疗和预防策略。

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.