Boston University School of Medicine, 650 Albany St, EBRC 646, Boston, MA, 02118, USA.
Skelet Muscle. 2012 Jun 7;2(1):10. doi: 10.1186/2044-5040-2-10.
Despite the success of highly active antiretroviral therapy (HAART), HIV infected individuals remain at increased risk for frailty and declines in physical function that are more often observed in older uninfected individuals. This may reflect premature or accelerated muscle aging.
Skeletal muscle gene expression profiles were evaluated in three uninfected independent microarray datasets including young (19 to 29 years old), middle aged (40 to 45 years old) and older (65 to 85 years old) subjects, and a muscle dataset from HIV infected subjects (36 to 51 years old). Using Bayesian analysis, a ten gene muscle aging signature was identified that distinguished young from old uninfected muscle and included the senescence and cell cycle arrest gene p21/Cip1 (CDKN1A). This ten gene signature was then evaluated in muscle specimens from a cohort of middle aged (30 to 55 years old) HIV infected individuals. Expression of p21/Cip1 and related pathways were validated and further analyzed in a rodent model for HIV infection.
We identify and replicate the expression of a set of muscle aging genes that were prematurely expressed in HIV infected, but not uninfected, middle aged subjects. We validated select genes in a rodent model of chronic HIV infection. Because the signature included p21/Cip1, a cell cycle arrest gene previously associated with muscle aging and fibrosis, we explored pathways related to senescence and fibrosis. In addition to p21/Cip1, we observed HIV associated upregulation of the senescence factor p16INK4a (CDKN2A) and fibrosis associated TGFβ1, CTGF, COL1A1 and COL1A2. Fibrosis in muscle tissue was quantified based on collagen deposition and confirmed to be elevated in association with infection status. Fiber type composition was also measured and displayed a significant increase in slow twitch fibers associated with infection.
The expression of genes associated with a muscle aging signature is prematurely upregulated in HIV infection, with a prominent role for fibrotic pathways. Based on these data, therapeutic interventions that promote muscle function and attenuate pro-fibrotic gene expression should be considered in future studies.
尽管高效抗逆转录病毒疗法（HAART）取得了成功，但 HIV 感染者仍然存在脆弱和身体功能下降的风险，这些情况在未感染的老年人中更为常见。这可能反映了肌肉过早或加速衰老。
评估了三个未感染的独立微阵列数据集（19 至 29 岁、40 至 45 岁和 65 至 85 岁）以及 HIV 感染者的肌肉数据集（36 至 51 岁）中的骨骼肌基因表达谱。使用贝叶斯分析，确定了一个由十个基因组成的肌肉衰老特征，该特征可将年轻的未感染肌肉与年老的未感染肌肉区分开来，其中包括衰老和细胞周期停滞基因 p21/Cip1（CDKN1A）。然后，在一组中年（30 至 55 岁）HIV 感染者的肌肉标本中评估了这十个基因特征。验证并进一步分析了 HIV 感染的啮齿动物模型中 p21/Cip1 和相关途径。
我们确定并复制了一组在 HIV 感染但未感染的中年患者中过早表达的肌肉衰老基因的表达。我们在慢性 HIV 感染的啮齿动物模型中验证了一些选定的基因。由于该特征包括 p21/Cip1，这是一种以前与肌肉衰老和纤维化相关的细胞周期停滞基因，因此我们探索了与衰老和纤维化相关的途径。除了 p21/Cip1，我们还观察到 HIV 相关的衰老因子 p16INK4a（CDKN2A）和纤维化相关的 TGFβ1、CTGF、COL1A1 和 COL1A2 的上调。根据胶原蛋白沉积对肌肉组织中的纤维化进行了定量，并证实与感染状态相关的纤维化增加。还测量了纤维类型组成，发现与感染相关的慢肌纤维显著增加。
与肌肉衰老特征相关的基因表达在 HIV 感染中过早上调，纤维化途径起着重要作用。基于这些数据，在未来的研究中应考虑使用促进肌肉功能和减弱促纤维化基因表达的治疗干预措施。
