Transcriptional Control of Skeletal Muscle Atrophy

骨骼肌萎缩是由于营养不足，衰老，某些药物和广泛的 医学疾病，包括癌症、糖尿病、心脏或肾衰竭以及急性或慢性感染。是 与增加的残疾，发病率以及死亡率有关，折磨着数百万美国人，占数千人的比例。 每年数十亿美元的医疗费用。此外，退伍军人预计将增加 与一般人群相比，由于与军事服务有关的伤害而导致的肌肉萎缩的患病率 以及他们的年龄。然而，目前还没有批准的药物治疗， 肌肉萎缩和控制肌肉质量的分子决定因素仍然不完全确定。使用 条件遗传工程，我们已经确定了一个令人惊讶的新作用的B细胞淋巴瘤6（BCL 6） 转录抑制子来维持肌肉质量。在此，我们建议全面剖析 BCL 6在肌肉中的表达及其表观基因调控。在目标1中，我们将测试BCL 6对肌肉蛋白质的影响 合成和降解、肌肉质量、肌纤维规格和代谢、力量和全身 能量平衡在目标2中，我们将定义BCL6的全基因组基因调控网络及其表达。 表观基因组、分子和生物化学机制来控制蛋白质稳态。这些研究将 揭示了新的分子见解和潜在的治疗途径，以减少骨骼肌损失的负担。

Skeletal muscle atrophy results from insufficient nutrition, aging, certain medications, and a wide range of medical illnesses including cancer, diabetes mellitus, heart or renal failure, and acute or chronic infections. It is linked to increased disability, morbidity, as well as mortality, afflicts millions of Americans, and accounts for tens of billions of dollars in annual healthcare costs. Moreover, veterans are projected to have an increased prevalence of muscle atrophy compared to the general population because of military service-related injuries and medical conditions as well as their older age. Yet, there are no currently approved medical therapies for muscle atrophy, and the molecular determinants that control muscle mass remain incompletely defined. Using conditional genetic engineering, we have identified a surprising new role for the B cell lymphoma 6 (BCL6) transcriptional repressor to maintain muscle mass. Herein, we propose to comprehensively dissect the function of BCL6 in muscle and its epigenomic regulation. In Aim 1, we will test the impact of BCL6 on muscle protein synthesis and degradation, muscle mass, myofiber specification and metabolism, strength, and whole body energy homeostasis. In Aim 2, we will define the genome-wide gene regulatory network for BCL6 and its epigenomic, molecular, and biochemical mechanisms for controlling proteostasis. Together, these studies will reveal new molecular insights and a potential therapeutic pathway to reduce the burden of skeletal muscle loss.