THE LEPTIN-IGF1 AXIS IN MUSCULOSKELETAL AGING

衰老与体重的减少有关，通常被称为老年厌食症，它伴随着肌肉量的减少（肌肉减少症）和骨质流失（骨质疏松症）。细胞因子样激素瘦素由包括脂肪和骨骼肌在内的外周组织分泌，瘦素缺乏与骨量减少以及肌肉质量和力量的损失有关。我们已经确定了一种动物模型，衰老的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。我们也首次表明，老年小鼠的肌肉骨骼组织显示增加的表达

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.