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 内科疾病，包括癌症、糖尿病、心脏或肾功能衰竭，以及急性或慢性感染。它是 与残疾、发病率和死亡率的增加有关，困扰着数百万美国人，占 每年数十亿美元的医疗成本。此外，退伍军人预计将有更多 与一般人群相比，与服兵役相关的损伤导致肌肉萎缩的患病率 健康状况以及他们的年龄。然而，目前还没有被批准的治疗方法 肌肉萎缩，以及控制肌肉质量的分子决定因素仍然没有完全确定。vbl.使用 条件基因工程，我们已经确定了B细胞淋巴瘤6(BCL6)的一个令人惊讶的新角色 转录抑制物，以维持肌肉质量。在此，我们建议对其功能进行全面剖析 BCL6在肌肉中的表达及其表观基因组调控。在目标1中，我们将测试BCL6对肌肉蛋白质的影响 合成和降解、肌肉质量、肌纤维规格和新陈代谢、力量和全身 能量平衡。在目标2中，我们将定义bcl6及其基因的全基因组基因调控网络。 控制蛋白平衡的表观基因组学、分子和生化机制。总而言之，这些研究将 揭示新的分子洞察力和潜在的治疗途径，以减轻骨骼肌损失的负担。

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.