ORCID Profile
0000-0002-1140-6204
Current Organisation
Karolinska Institutet
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Publisher: Wiley
Date: 17-06-2023
Abstract: Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform‐specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN‐KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs‐iOPN‐KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN‐KO mice compared to control mice. Accordingly, adult OPN‐KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin‐related proteins. In contrast, neonatal oligodendrocytes from OLs‐iOPN‐KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs‐iOPN‐KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform‐specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.
Publisher: Elsevier BV
Date: 03-2021
Publisher: Elsevier BV
Date: 12-2022
Publisher: Cold Spring Harbor Laboratory
Date: 03-10-2020
DOI: 10.1101/2020.10.03.323964
Abstract: The fast skeletal muscle protein α-actinin-3 is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in the ACTN3 gene (R577X) 1 . The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance 1,2 . Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX in iduals displayed a shift towards more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering 3,4 . Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX in iduals. Thus, this study provides a clear mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.
Publisher: Cold Spring Harbor Laboratory
Date: 30-03-2021
DOI: 10.1101/2021.03.29.437546
Abstract: Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. Here, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca 2+ handling in adult mouse skeletal muscle fibers. Adult skeletal muscle fibers were isolated from mouse toe muscle either by collagenase-induced dissociation of the ECM or by mechanical dissection that leaves the contiguous ECM intact. Experiments were generally performed four hours after cell isolation. At this time, there were striking differences in the gene expression patterns between fibers isolated with the two methods 24h after cell isolation, enzymatically dissociated fibers had transcriptomic signatures resembling dystrophic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria in enzymatically dissociated than in mechanically dissected fibers. Similar increases in free cytosolic [Ca 2+ ] during repeated tetanic stimulation were accompanied by marked mitochondrial Ca 2+ uptake only in enzymatically dissociated muscle fibers. The aberrant mitochondrial Ca 2+ uptake was partially prevented by the mitochondrial Ca 2+ uniporter inhibitor Ru360 and by cyclosporine A and NV556, which inhibit the mitochondrial protein Ppif (also called cyclophilin D). Importantly, inhibition of Ppif with NV556 significantly improved survival of mice with mitochondrial myopathy in which muscle mitochondria take up excessive amounts of Ca 2+ even with an intact ECM. In conclusion, skeletal muscle fibers isolated by collagenase-induced dissociation of the ECM display aberrant mitochondrial Ca 2+ uptake, which involves a Ppif-dependent mitochondrial Ca 2+ influx resembling that observed in mitochondrial myopathies.
Publisher: Elsevier BV
Date: 06-2020
No related grants have been discovered for Volker Lauschke.