Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain

Abstract

Mechano growth factor (MGF) is a splice variant of IGF-1 first described in skeletal muscle. MGF induces muscle cell proliferation in response to muscle stress and injury. In control mice we found endogenous expression of MGF in neurogenic areas of the brain and these levels declined with age. To better understand the role of MGF in the brain, we used transgenic mice that constitutively overexpressed MGF from birth. MGF overexpression significantly increased the number of BrdU+ proliferative cells in the dentate gyrus (DG) of the hippocampus and subventricular zone (SVG). Although MGF overexpression increased the overall rate of adult hippocampal neurogenesis at the proliferation stage it did not alter the distribution of neurons at post-mitotic maturation stages. We then used the lac-operon system to conditionally overexpress MGF in the mouse brain beginning at 1, 3 and 12 months with histological and behavioral observation at 24 months of age. With conditional overexpression there was an increase of BrdU+ proliferating cells and BrdU+ differentiated mature neurons in the olfactory bulbs at 24 months when overexpression was induced from 1 and 3 months of age but not when started at 12 months. This was associated with preserved olfactory function. In vitro, MGF increased the size and number of neurospheres harvested from SVZ-derived neural stem cells (NSCs). These findings indicate that MGF overexpression increases the number of neural progenitor cells and promotes neurogenesis but does not alter the distribution of adult newborn neurons at post-mitotic stages. Maintaining youthful levels of MGF may be important in reversing age-related neuronal loss and brain dysfunction.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0304-0) contains supplementary material, which is available to authorized users.

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice

“…In contrast, reduced levels of GluA2 in the dentate gyrus of the hippocampus have been associated with memory loss in aged monkeys (Hara et al 2012). Likewise, short-term IN IGF-1 showed beneficial effects on neurogenesis in old mice, similar to previous studies in which IGF-1 was introduced by di fferent m eans in aged rodents (Lichtenwalner et al 2001;Perez-Martin et al 2010;Tang et al 2017). Furthermore, based upon the~30% increase in brain weight and volume in mice that were chronically overexposed to IGF-1 centrally, along with the marked increase in forebrain Akt and S6 activation, it seems plausible that the inability of IGF-1 to preserve cognitive function in these mice may have simply resulted from long-term overstimulation of this pathway.…”

https://iupress.istanbul.edu.tr/en/journal/experimed/article/yetiskin-norogenez-ve-norodejeneratif-hastaliklarda-buyume-faktorlerinin-rolu

“…Mekanik büyüme faktörü (MGF) ile yapılan bir çalışmada hipokampus ve OB'de bulunan NKH popülasyonunu artırarak nörogenez üzerinde etkisi olduğu gösterilmiştir. Elde edilen verilerde MGF'nin, nöral progenitör hücrelerin korunmasını ya da proliferasyonunu sağlayarak NKH'leri arttırdığı gösterilmiştir (103).…”

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

“…Furthermore, in mouse brain, MGF promotes neurogenesis and increases the number of neural progenitor cells, preventing neuronal attrition and brain dysfunction in aging mice. In turn, it does not affect adult new-born neurons at post-mitotic stages [ 163 ]. A detailed mechanism of the neuroprotective activity of an MGF derivative via Protein Kinase Cϵ (PKCϵ) activity and Nuclear Factor (NF) E2-related factor 2 (Nrf2) was also described [ 164 ].…”