Overcoming Disuse Atrophy and Osteoporosis in Hibernating Mammals

描述（由申请人提供）：在人类和大多数哺乳动物中，骨骼负荷减少导致肌肉萎缩和骨质流失。废用性肌肉萎缩和骨质疏松症是长期固定和卧床休息患者的重要临床问题。熊和地松鼠在冬眠期间基本上是不活动的，但它们的骨量没有减少，肌肉萎缩也没有长时间不活动所造成的损失。这表明冬眠的哺乳动物对肌肉骨骼的废用具有独特的自然适应性。虽然冬眠的熊和地松鼠的骨量保存和肌肉萎缩的衰减已经被记录下来，但这种重要适应的分子机制尚不清楚。我们的目标是通过转录变化确定与生理相关的候选途径，并了解防止冬眠哺乳动物废用性肌肉萎缩和骨质流失的分子机制。下一代测序工具的优势将用于对冬季冬眠和夏季活动动物的骨骼和肌肉的转录变化进行大规模筛选。全基因组转录谱分析将检测到足够数量的差异表达基因，以进行全面的途径分析，阐明转录变化的功能意义。通过比较两个进化距离较远、具有不同冬眠模式的物种间共调控基因所富集的功能基因群和通路，有望揭示具有开发潜力的通用转录程序，以改善包括人类在内的非冬眠哺乳动物的失用性肌肉萎缩和骨质疏松症的治疗和预防。

DESCRIPTION (provided by applicant): Reduced skeletal loading leads to muscle atrophy and bone loss in humans and most mammals. Disuse muscle atrophy and osteoporosis represent significant clinical problem for patients during prolonged periods of immobilization and bed rest. Bears and ground squirrels are largely inactive during hibernation, but they show no loss in bone mass and less muscle atrophy than would be anticipated over such a prolonged period of physical inactivity. This suggests that hibernating mammals have unique natural adaptation to musculoskeletal disuse. Although preservation of bone mass and attenuation of muscle atrophy in hibernating bears and ground squirrels have been documented, molecular mechanisms underlying this important adaptation are not known. Our goal is to identify through transcriptional changes physiologically relevant candidate pathways and understand molecular mechanisms preventing disuse muscle atrophy and bone loss in hibernating mammals. Advantage of the next generation sequencing tools will be used to conduct large scale screens of transcriptional changes in bone and muscle comparing winter hibernating and summer active animals. Genome-wide transcriptional profiling will detect sufficiently large number of differentially expressed genes for comprehensive pathway analysis elucidating functional significance of transcriptional changes. Comparison of functional gene groups and pathways enriched by co regulated genes between two evolutionary distant species with different hibernation modes is expected to reveal general transcriptional program with untapped potential for development of improved treatment and prevention of disuse muscle atrophy and osteoporosis in non-hibernating mammals, including humans. .