Overcoming Disuse Atrophy and Osteoporosis in Hibernating Mammals

描述(申请人提供)：骨骼负荷减少会导致人类和大多数哺乳动物的肌肉萎缩和骨质丢失。在长时间的制动和卧床期间，废用性肌肉萎缩和骨质疏松症是患者的主要临床问题。熊和地松鼠在冬眠期间基本上不活动，但它们在如此长时间的不活动中表现出的骨量没有损失，肌肉萎缩也比预期的要少。这表明冬眠哺乳动物对肌肉骨骼的废弃有独特的自然适应。虽然冬眠熊和地松鼠的骨量保护和肌肉萎缩的减轻已经被记录在案，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丢失的分子机制。下一代测序工具的优势将用于对骨骼和肌肉的转录变化进行大规模筛选，比较冬季冬眠和夏季活动的动物。全基因组转录图谱将检测足够多的差异表达基因，用于全面的途径分析，阐明转录变化的功能意义。对两个不同冬眠模式的进化遥远物种之间由共同调节基因丰富的功能基因组和途径的比较，有望揭示通用的转录程序，在改进包括人类在内的非冬眠哺乳动物的治疗和预防废用性肌肉萎缩和骨质疏松症方面具有尚未开发的潜力。。

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. .