The role of mitochondrial remodeling in neurodegenerative diseases

Neurochemistry International, Journal Year: 2025, Volume and Issue: unknown, P. 105927 - 105927

Published: Jan. 1, 2025

Language: Английский

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From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders

Biology, Journal Year: 2024, Volume and Issue: 13(9), P. 719 - 719

Published: Sept. 12, 2024

Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's (PD), primarily affect the central nervous system, leading to progressive neuronal loss motor cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe wasting as result of neuron degeneration, well alterations gene expression, protein aggregation, oxidative stress. Muscle atrophy mitochondrial dysfunction are observed AD, which may exacerbate decline due systemic metabolic dysregulation. PD patients exhibit fiber atrophy, altered composition, α-synuclein aggregation within cells, contributing symptoms progression. Systemic inflammation impaired degradation pathways common among disorders, highlighting key player Understanding muscle-related changes offers potential therapeutic avenues, such targeting function, reducing inflammation, promoting regeneration with exercise pharmacological interventions. This review emphasizes importance considering an integrative approach neurodegenerative research, both peripheral pathological mechanisms, order develop more effective treatments improve patient outcomes.

Language: Английский

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Exosomes in Regulating miRNAs for Biomarkers of Neurodegenerative Disorders

Molecular Neurobiology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Language: Английский

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Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Patients: Insights from High-Resolution Respirometry

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1294 - 1294

Published: June 11, 2024

Amyotrophic lateral sclerosis is a severe neurodegenerative disease whose exact cause still unclear. Currently, research attention turning to the mitochondrion as critical organelle of energy metabolism. Current knowledge sufficient confirm involvement mitochondria in pathophysiology disease, since are involved many processes cell; however, mechanism We used peripheral blood mononuclear cells isolated from whole fresh patients with amyotrophic for measurement and matched an age- sex-matched set healthy subjects. The group consisted examined diagnosed at neurological clinic University Hospital Martin. controls individuals who were actively searched, selected on basis age sex. 26 sporadic forms ALS (13 women, 13 men), based definitive criteria El Escorial. average was 54 years, 56 years. high-resolution O2K respirometry method, Oxygraph-2k, measure mitochondrial respiration. Basal respiration lower by 29.48%, pyruvate-stimulated (respiratory chain complex I) 29.26%, maximal respiratory capacity 28.15%. decrease succinate-stimulated II) 26.91%. Our data changes patients, manifested reduced function I II chain. These defects enough this disease’s hypothesized damage. Therefore, interest future should be directed towards deeper understanding complexes disease. This could develop new biomarkers diagnostics subsequent therapeutic interventions.

Language: Английский

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Muscle-specific Bet1L knockdown induces neuromuscular denervation, motor neuron degeneration, and motor dysfunction in a rat model of familial ALS

Frontiers in Neuroscience, Journal Year: 2025, Volume and Issue: 19

Published: Jan. 17, 2025

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by specific loss of motor neurons in the spinal cord and brain stem. Although ALS has historically been as neuron disease, there evidence that degenerate retrograde manner, beginning periphery at junctions (NMJs) skeletal muscle. We recently reported vesicle trafficking protein Bet1L (Bet1 Golgi Vesicular Membrane Trafficking Protein Like) new molecule possibly linked to NMJ degeneration ALS. In this study, we tested hypothesis gene silencing muscle could influence integrity, function, survival rat model familial (SOD1G93A transgenic). Small interfering RNA (siRNA) targeting was injected on weekly basis into hindlimb pre-symptomatic wild-type (WT) rats. After 3 weeks, intramuscular siRNA injection significantly increased number denervated NMJs knockdown decreased size lumbar cord, which innervated siRNA-injected hindlimb. Impaired function identified hindlimbs Notably, effects were more significant rats when compared WT Together, induces denervation NMJs, but also accelerates progression Our results provide support potential roles key maintenance pathogenesis.

Language: Английский

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Hidden players in the metabolic vulnerabilities of amyotrophic lateral sclerosis

Trends in Endocrinology and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Amyotrophic lateral sclerosis (ALS) is a complex and rapidly progressive motor neuron disorder with fatal outcome. Despite the remarkable progress in understanding ALS pathophysiology, which has significantly contributed to clinical trial design, remains disabling life-shortening condition. The non-motor features of ALS, including nutritional status, energy expenditure, metabolic imbalance, are increasingly gaining attention. Indeed, bioenergetic failure mitochondrial dysfunction patients impact not only high energy-demanding neurons but also organs brain areas long considered irrelevant disease. As such, here we discuss how considering balance reshaping research on this disease, opening path novel targetable opportunities for its treatment.

Language: Английский

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Extracellular Vesicles from Regenerating Skeletal Muscle Mitigate Muscle Atrophy in an Amyotrophic Lateral Sclerosis Mouse Model

Cells, Journal Year: 2025, Volume and Issue: 14(6), P. 464 - 464

Published: March 20, 2025

Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by progressive motor neuron degeneration and muscle atrophy, with no effective treatments available. Chronic inflammation, which impairs regeneration promotes proteolysis, key contributor to ALS-related atrophy promising therapeutic target. Here, we applied extracellular vesicles (EVs) derived from regenerating skeletal muscles 14 days post-acute injury (CTXD14SkM-EVs), possess unique anti-inflammatory profile, target defects in ALS. We found that CTXD14SkM-EVs enhanced myoblast differentiation fusion cellular muscle-wasting model induced pro-inflammatory cytokine tumor necrosis factor alpha. Intramuscular administration of these EVs into an ALS mouse mitigated promoting regeneration, shifting macrophage polarization M1 M2 state, suppressing the aberrant Nuclear Factor Kappa B (NF-κB) signaling, driver protein degradation. These results underscore potential muscle-derived for combating

Language: Английский

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Comparative Study of Structural and Functional Rearrangements in Skeletal Muscle Mitochondria of SOD1-G93A Transgenic Mice at Pre-, Early-, and Late-Symptomatic Stages of ALS Progression

Frontiers in Bioscience-Landmark, Journal Year: 2025, Volume and Issue: 30(3)

Published: March 18, 2025

Background: Amyotrophic lateral sclerosis (ALS) is a progressive multisystem disease characterized by limb and trunk muscle weakness that attributed, in part, to abnormalities mitochondrial ultrastructure impaired functions. This study investigated the time course of structural functional rearrangements skeletal mitochondria combination with motor impairments Tg (copper-zinc superoxide dismutase enzyme (SOD1) G93A) dl1/GurJ (referred as SOD1-G93A/low) male mice, familial ALS model, compared non-transgenic littermates. Methods: The neurological status functions were assessed weekly using paw grip endurance method grid suspension test two-limb four-limb tasks. Transmission electron microscopy followed quantitative analysis was performed ultrastructural alterations quadriceps femoris. Functional high-resolution Oxygraph-2k (O2K) respirometry methods for assessing calcium retention capacity index content lipid peroxidation products freshly isolated preparations. Results: Based on behavioral phenotyping data, specific age groups identified: postnatal day 56 (P56) (n = 10–11), 84 (P84) 156 (P154) 10–12), representing pre-symptomatic, early-symptomatic late-symptomatic stages progression SOD1-G93A/low respectively. Electron showed mosaic destructive changes subsarcolemmal fibers femoris from 84-day-old mice. Morphometric revealed an elevation mean size SOD1-G93A mice at P84 P154. In addition, P154 transgenic group demonstrated decrease sarcomere width number per unit area. At symptomatic stage, exhibited decreased respiratory control ratio, ADP-stimulated, uncoupled respiration rates muscle, measured respirometry. parallel, lower increased levels control. Conclusions: Taken together, these results indicate stage-dependent associated defective oxidative phosphorylation, homeostasis, damage mouse which appears be promising direction development therapies ALS.

Language: Английский

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Trimetazidine, a promising drug for amyotrophic lateral sclerosis, modulates Ca2+ influx in spinal neurons

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

The metabolic modulator trimetazidine (TMZ) is an antianginal recently found to improve skeletal muscle performance in mice models of sarcopenia and Amyotrophic Lateral Sclerosis (ALS). mechanism underlying the effect TMZ on locomotor activity has been proposed rely its ability enhance efficiency with a consequent improvement myogenesis neuromuscular junction (NMJ) function. However, although promising therefore under clinical trials, action not clearly disclosed; here we hypothesized that it might involve modulation neuronal Ca²⁺ flows. We studied dynamics in vivo, by using transgenic zebrafish line Tg(neurod1:GCaMP6f) which expression indicator GCaMP allows visualize neurons larvae. By this elegant tool, demonstrated, for first time, promotes influx spinal likely enhancing motor neuron firing, correlates enhanced drug. Even though elevated intracellular levels have often associated neurotoxicity, unclear if excitability features ALS are compensatory or pathological. Therefore, potentially contribute counteract neurodegeneration modulating fluxes, transiently selectively as well NMJ function, without increasing overall excitability. This further supports repurposing treatment other conditions characterized impairment, such aging.

Language: Английский

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New perspectives of the role of skeletal muscle derived extracellular vesicles in the pathogenesis of amyotrophic lateral sclerosis: the ‘dying back’ hypothesis

Journal of Extracellular Biology, Journal Year: 2024, Volume and Issue: 3(11)

Published: Nov. 1, 2024

Abstract Amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord, characterized by muscle weakness, paralysis ultimately, respiratory failure. The exact causes of ALS are not understood, though it believed to combine genetic environmental factors. Until now, was admitted motor neurons (MN) cord degenerate, leading weakness paralysis. However, as symptoms typically begin with or stiffness, new hypothesis has recently emerged explain development pathology, is, ‘dying back hypothesis’, suggesting this degeneration starts at connections between MN muscles, resulting loss function. Over time, damage extends along length MN, ultimately affecting their cell bodies brain. While dying provides potential framework for understanding progression ALS, mechanisms underlying remain complex fully understood. In review, we positioning role extracellular vesicles actors development.

Language: Английский

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