Recovery of muscle mass and muscle oxidative phenotype following disuse does not require GSK-3 inactivation.
废用后恢复肌肉质量和肌肉氧化表型不需要 GSK-3 失活。
- 作者列表："Theeuwes WF","Pansters NAM","Gosker HR","Schols AMWJ","Verhees KJP","de Theije CC","van Gorp RHP","Kelders MCJM","Ronda O","Haegens A","Remels AHV","Langen RCJ
BACKGROUND:Physical inactivity contributes to muscle wasting and reductions in mitochondrial oxidative phenotype (OXPHEN), reducing physical performance and quality of life during aging and in chronic disease. Previously, it was shown that inactivation of glycogen synthase kinase (GSK)-3β stimulates muscle protein accretion, myogenesis, and mitochondrial biogenesis. Additionally, GSK-3β is inactivated during recovery of disuse-induced muscle atrophy. AIM:Therefore, we hypothesize that GSK-3 inhibition is required for reloading-induced recovery of skeletal muscle mass and OXPHEN. METHODS:Wild-type (WT) and whole-body constitutively active (C.A.) Ser21/9 GSK-3α/β knock-in mice were subjected to a 14-day hind-limb suspension/14-day reloading protocol. Soleus muscle mass, fiber cross-sectional area (CSA), OXPHEN (abundance of sub-units of oxidative phosphorylation (OXPHOS) complexes and fiber-type composition), as well as expression levels of their main regulators (respectively protein synthesis/degradation, myogenesis and peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) signaling) were monitored. RESULTS:Subtle but consistent differences suggesting suppression of protein turnover signaling and decreased expression of several OXPHOS sub-units and PGC-1α signaling constituents were observed at baseline in C.A. GSK-3 versus WT mice. Although soleus mass recovery during reloading occurred more rapidly in C.A. GSK-3 mice, this was not accompanied by a parallel increased CSA. The OXPHEN response to reloading was not distinct between C.A. GSK-3 and WT mice. No consistent or significant differences in reloading-induced changes in the regulatory steps of protein turnover, myogenesis or muscle OXPHEN were observed in C.A. GSK-3 compared to WT muscle. CONCLUSION:This study indicates that GSK-3 inactivation is dispensable for reloading-induced recovery of muscle mass and OXPHEN.
背景: 身体不活动有助于肌肉萎缩和线粒体氧化表型 (OXPHEN) 的减少，降低衰老和慢性病期间的身体表现和生活质量。以前，研究表明糖原合成酶激酶 (GSK)-3 β 的失活刺激肌肉蛋白增生、肌生成和线粒体生物合成。此外，在废用诱导的肌肉萎缩恢复过程中，gsk-3 β 失活。 目的: 因此，我们假设 GSK-3 抑制是重新负荷诱导的骨骼肌质量和 OXPHEN 恢复所必需的。 方法: 野生型 (WT) 和全身组成性活性 (C.A.)Ser21/9 gsk-3 α/β 敲入小鼠接受 14 天后肢悬吊/14 天重装方案。比目鱼肌质量、纤维横截面积 (CSA) 、 OXPHEN (氧化磷酸化 (OXPHOS) 复合物亚单位丰度和纤维类型组成) 、以及其主要调控因子 (分别为蛋白合成/降解、肌生成和过氧化物酶体增殖物激活受体-γ 共激活因子-1 α (pgc-1 α) 信号) 的表达水平进行监测。 结果: 在 C.A.基线时观察到细微但一致的差异，提示抑制蛋白转换信号和降低几个 OXPHOS 亚单位和 pgc-1 α 信号成分的表达。GSK-3 与 WT 小鼠。虽然重装过程中比目鱼肌大量恢复在 C.A 中发生得更快。GSK-3 小鼠，这不是伴随着平行增加的 CSA。OXPHEN 对重装的反应在 C.A.之间没有区别。GSK-3 和 WT 小鼠。在 C.A.中未观察到蛋白周转、肌生成或肌肉 OXPHEN 的调控步骤的再负荷诱导变化存在一致或显著差异。与 WT 肌肉相比 GSK-3。 结论: 本研究表明，GSK-3 失活对于再负荷诱导的肌肉质量恢复和 OXPHEN 是可有可无的。
METHODS:Purpose Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). Methods We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. Results Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33–26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. Conclusion Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.
METHODS::Growth hormone-secreting pituitary adenoma (GHPA), a benign endocrine tumor located in the base of the skull, results in acromegaly. In addition to the mass effect of the tumor itself in the sellar region, GHPA can lead to the overgrowth of almost every organ. Previous findings indicated that the processes underlying acromegaly were partly attributable to hyperactivity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis. However, the mechanisms driving this syndrome remains largely unknown. Additionally, the roles of GHPA-derived exosomes, which contain functional microRNAs and proteins that manipulate target cell proliferation and differentiation in distal extremities, are also unknown. In this study, we demonstrated that GHPA exosomes promote bone formation in vitro and trabecula number in vivo. The mechanism of increased trabecula formation may be attributable to GHPA exosome-induced osteoblast proliferation via increased cell viability and DNA replication. We further discovered that exosomal hsa-miR-21-5p plays a distinct role from the GH/IGF-1 axis in these processes. Accordingly, the results of this study provide a novel mechanism whereby GHPA influences distal extremities and a new perspective for treating GHPA.
METHODS:BACKGROUND:Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. AIM:To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. METHODS:Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS:Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). CONCLUSION:1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. CLINICAL TRIALS REGISTRATION:NCT00647179.