Dataset Information

Small extracellular vesicles from skeletal muscle cells (human)

ABSTRACT: Quantitative comparison of the protein load of small extracellular vesicles released from human skeletal muscle cells prior and after electric pulse stimulation.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Suspension Culture

SUBMITTER: Stefan Lehr

LAB HEAD: Stefan Lehr

PROVIDER: PXD020278 | Pride | 2022-02-15

REPOSITORIES: Pride

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Publications

Metabolic responsiveness to training depends on insulin sensitivity and protein content of exosomes in insulin-resistant males.

Apostolopoulou Maria M Mastrototaro Lucia L Hartwig Sonja S Pesta Dominik D Straßburger Klaus K de Filippo Elisabetta E Jelenik Tomas T Karusheva Yanislava Y Gancheva Sofiya S Markgraf Daniel D Herder Christian C Nair K Sreekumaran KS Reichert Andreas S AS Lehr Stefan S Müssig Karsten K Al-Hasani Hadi H Szendroedi Julia J Roden Michael M

Science advances 20211008 41

High-intensity interval training (HIIT) improves cardiorespiratory fitness (VO<sub>2</sub>max), but its impact on metabolism remains unclear. We hypothesized that 12-week HIIT increases insulin sensitivity in males with or without type 2 diabetes [T2D and NDM (nondiabetic humans)]. However, despite identically higher VO<sub>2</sub>max, mainly insulin-resistant (IR) persons (T2D and IR NDM) showed distinct alterations of circulating small extracellular vesicles (SEVs) along with lower inhibitory ...[more]

PMID: 34623918

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Project description:Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with progressive loss of dopaminergic neurons in the substantia nigra, and accumulation of aggregates of α-synuclein. However, the sequence of molecular events that proceed from the SNCA mutation during development, to its end stage pathology is unknown. Utilising human induced pluripotent stem cells (hiPSCs) with SNCA mutations, we resolved the temporal sequence of pathophysiological events that occur during neuronal differentiation in order to discover the early, and likely causative, events in synucleinopathies. We adapted a small molecule-based protocol that generates highly enriched midbrain dopaminergic (mDA) neurons (>80%). We characterised their molecular identity using single-cell RNA sequencing and their functional identity through the synthesis and secretion of dopamine, the ability to generate action potentials, and form functional synapses and networks. RNA velocity analyses confirmed the developmental transcriptomic trajectory of midbrain neural precursors into different mDA neuronal clusters. To characterise the synucleinopathy, we adopted super-resolution methods to determine the number, size, and structure of aggregates in SNCA-mutant mDA neurons. By day 27 of differentiation, prior to maturation to mDA neurons of molecular and functional identity, we demonstrate the formation of small aggregates; specifically, β-sheet rich oligomeric aggregates, in SNCA-mutant midbrain immature neurons. The aggregation progresses over time to accumulate phosphorylated and fibrillar aggregates. When the midbrain neurons were functional, we observed impaired intracellular calcium signalling, evidenced with an increased basal calcium level and impairments in both cytosolic and mitochondrial calcium rearrangements. Once midbrain identity fully developed, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling as well as an upregulation of mitophagy and autophagy. In addition, SNCA-mutant neurons displayed pathophysiological excitability, revealed as a depolarised resting membrane potential, an increased input resistance, and impaired firing properties. Ultimately these multiple cellular stresses lead to an increase in cell death by day 62 post-differentiation. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD, and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.

Dataset Information

Small extracellular vesicles from skeletal muscle cells (human)

Publications

Metabolic responsiveness to training depends on insulin sensitivity and protein content of exosomes in insulin-resistant males.

Similar Datasets

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