Intramural Research Program, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
Cells. 2024 Nov 18;13(22):1903. doi: 10.3390/cells13221903.
Insulin resistance, stem cell dysfunction, and muscle fiber dystrophy are all age-related events in skeletal muscle (SKM). However, age-related changes in insulin isoforms and insulin receptors in myogenic progenitor satellite cells have not been studied. Since SKM is an extra-pancreatic tissue that does not express mature insulin, we investigated the levels of insulin receptors (INSRs) and a novel human insulin upstream open reading frame (INSU) at the mRNA, protein, and anatomical levels in Baltimore Longitudinal Study of Aging (BLSA) biopsied SKM samples of 27-89-year-old (yrs) participants. Using RT-qPCR and the MS-based selected reaction monitoring (SRM) assay, we found that the levels of INSR and INSU mRNAs and the proteins were positively correlated with the age of human SKM biopsies. We applied RNAscope fluorescence in situ hybridization (FISH) and immunofluorescence (IF) to SKM cryosections and found that INSR and INSU were co-localized with PAX7-labeled satellite cells, with enhanced expression in SKM sections from an 89 yrs old compared to a 27 yrs old. We hypothesized that the SKM aging process might induce compensatory upregulation of INSR and re-expression of INSU, which might be beneficial in early embryogenesis and have deleterious effects on proliferative and myogenic satellite cells with advanced age.
胰岛素抵抗、干细胞功能障碍和肌肉纤维营养不良都是骨骼肌（SKM）与年龄相关的事件。然而，成肌祖细胞卫星细胞中胰岛素同工型和胰岛素受体的年龄相关性变化尚未得到研究。由于 SKM 是一种不表达成熟胰岛素的胰腺外组织，我们研究了巴尔的摩纵向衰老研究（BLSA）中 27-89 岁参与者的 SKM 活检样本中胰岛素受体（INSR）和新型人胰岛素上游开放阅读框（INSU）在 mRNA、蛋白质和解剖水平上的水平。使用 RT-qPCR 和基于 MS 的选择反应监测（SRM）测定法，我们发现 INSR 和 INSU mRNA 水平以及蛋白质水平与人类 SKM 活检的年龄呈正相关。我们应用 RNAscope 荧光原位杂交（FISH）和免疫荧光（IF）对 SKM 冷冻切片进行检测，发现 INSR 和 INSU 与 PAX7 标记的卫星细胞共定位，与 27 岁相比，89 岁 SKM 切片中的表达增强。我们假设 SKM 衰老过程可能会诱导 INSR 的代偿性上调和 INSU 的重新表达，这可能对早期胚胎发生有益，而对高龄增殖和肌源性卫星细胞则具有有害影响。
