REDUCING PLASMA HIV RNA IMPROVES MUSCLE AMINO ACID METABOLISM

减少血浆 HIV RNA 改善肌肉氨基酸代谢

• 批准号: 7355251
• 负责人: KEVIN E YARASHESKI
• 金额: $ 1.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355251
• 关键词: REDUCING; PLASMA; HIV; RNA; IMPROVES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We reported (Yarasheski KE, Zachwieja JJ, Gischler J, Crowley J, Horgan MM, and Powderly WG. Am J Physiol Endocrinol Metab 275: E577-E583, 1998) that AIDS muscle wasting was associated with an inappropriately low rate of muscle protein synthesis and an elevated glutamine rate of appearance (Ra Gln). We hypothesized that high plasma HIV RNA caused dysregulation of muscle amino acid metabolism. We determined whether a reduction in HIV RNA ( 1 log) increased muscle protein synthesis rate and reduced Ra Gln and muscle proteasome activity in 10 men and 1 woman (22-57 yr, 60-108 kg, 17-33 kg muscle) with advanced HIV (CD4 = 0-311 cells/¿l; HIV RNA = 10-375 x 103 copies/ml). We utilized stable isotope tracer methodologies ([13C]Leu and [15N]Gln) to measure the fractional rate of mixed muscle protein synthesis and plasma Ra Gln in these subjects before and 4 mo after initiating their first or a salvage antiretroviral therapy regimen. After treatment, median CD4 increased (98 vs. 139 cells/¿l, P = 0.009) and median HIV RNA was reduced (155,828 vs. 100 copies/ml, P = 0.003). Mixed muscle protein synthesis rate increased (0.062 ¿ 0.005 vs. 0.078 ¿ 0.006%/h, P = 0.01), Ra Gln decreased (387 ¿ 33 vs. 323 ¿ 15 ¿mol?kg fat-free mass -1 h -1, P = 0.04), and muscle proteasome chymotrypsin-like catalytic activity was reduced 14% (P = 0.03). Muscle mass was only modestly increased (1 kg, P = not significant). We estimated that, for each 10,000 copies/ml reduction in HIV RNA, 3 g of additional muscle protein are synthesized per day. These findings suggest that reducing HIV RNA increases muscle protein synthesis and reduces muscle proteolysis, but muscle protein synthesis relative to whole body protein synthesis rate is not restored to normal, so muscle mass is not substantially increased.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。我们报道（Yarasheski KE、Zachwieja JJ、Gischler J、Crowley J、Horgan MM 和 Powderly WG. Am J Physiol Endocrinol Metab 275：E577-E583，1998）艾滋病肌肉萎缩与肌肉蛋白合成率过低和谷氨酰胺出现率 (Ra Gln) 升高有关。我们假设高血浆 HIV RNA 导致肌肉氨基酸代谢失调。我们确定了 10 名男性和 1 名女性（22-57 岁，60-108 kg，17-33 kg 肌肉）晚期 HIV（CD4 = 0-311 个细胞/¿l；HIV RNA = 10-375 x 103 拷贝/ml）中 HIV RNA 的减少（1 log）是否会增加肌肉蛋白合成率并降低 Ra Gln 和肌肉蛋白酶体活性。我们利用稳定同位素示踪方法（[13C]Leu 和 [15N]Gln）来测量这些受试者在开始第一个或挽救性抗逆转录病毒治疗方案之前和之后 4 个月的混合肌肉蛋白合成和血浆 Ra Gln 的分数率。治疗后，中位 CD4 增加（98 vs. 139 个细胞/μl，P = 0.009），中位 HIV RNA 减少（155,828 vs. 100 个拷贝/ml，P = 0.003）。混合肌蛋白合成率增加(0.062¿0.005 vs.0.078¿0.006%/h,P=0.01)，Ra Gln降低(387¿33 vs.323¿15¡mol?kg去脂质量-1 h -1，P=0.04)，肌肉蛋白酶体胰凝乳蛋白酶样催化活性降低14%（P = 0.03）。肌肉质量仅略有增加（1 kg，P = 不显着）。我们估计，HIV RNA 每减少 10,000 拷贝/ml，每天就会额外合成 3 g 肌肉蛋白。这些发现表明，减少HIV RNA会增加肌肉蛋白合成并减少肌肉蛋白水解，但肌肉蛋白合成相对于全身蛋白合成率并未恢复至正常，因此肌肉质量并未大幅增加。