Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 492 - 492

Published: March 12, 2024

Amyotrophic lateral sclerosis (ALS) is a mysterious lethal multisystem neurodegenerative disease that gradually leads to the progressive loss of motor neurons. A recent non-contact dying-back injury mechanism theory for ALS proposed primary damage an acquired irreversible intrafusal proprioceptive terminal Piezo2 channelopathy with underlying genetic and environmental risk factors. Underpinning this excessively prolonged mechanotransduction under allostasis may induce dysfunctionality in mitochondria, leading channelopathy. This microinjury suggested provide one gateway from physiology pathophysiology. The chronic, but not irreversible, form implicated many diseases unknown etiology. Dry eye them where replenishing synthetic proteoglycans promote nerve regeneration. Syndecans, especially syndecan-3, are as first critical link hierarchical ordered depletory pathomechanism proton-collecting/distributing antennas; hence, they play role onset. Even more importantly, shedding or charge-altering variants Syndecan-3 contribute channelopathy-induced disruption Piezo2-initiated proton-based ultrafast long-range signaling through VGLUT1 VGLUT2. Thus, these alterations only cause hippocampus conscious proprioception, could disrupt feedback motoneurons. Correspondingly, inert signaled skeletal system coming light be progressively lost ALS. In addition, functional MyoD family inhibitor proteins, auxiliary subunits Piezo2, theorized channelopathy, explain how microinjured ion channels evolve principal transcription activators.

Language: Английский

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Likely pathogenic variants of SDC3, KCNA2, KCNK1, KCNK16 and HSF1 are in support of acquired irreversible PIEZO2 channelopathy in ALS onset

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

Published: Jan. 3, 2025

Amyotrophic lateral sclerosis is a multisystem progressive neurodegenerative disease. A recent theory of ALS proposed that the disease initiating primary damage an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. Underpinning this these ion channels initiate ultrafast proton-based oscillatory signaling to motor neurons through VGLUT1 hippocampus VGLUT2. This may gradually degenerate in which process K_v1.2 are depleted. Furthermore, it also depletes heat shock transcription factor-1 hippocampus, hence negatively affecting adult hippocampal neurogenesis. In addition, not only PIEZO2-PIEZO2 crosstalk fully disrupted progressively between afferent terminals due lost initiated cross-coupled Huygens synchronization, but PIEZO2-PIEZO1 on periphery. Syndecans, especially syndecan-3 nervous system, critical players maintenance PIEZO crosstalk. The detected charge altering variants likely promotes impairment crosstalk, loss as well. Variants KCNA2 facilitate faster function when prevails, mention potassium current rectifying encoding KCNK1 KCNK16 propel provide autoimmune-like pathogenic background. Moreover, diminishing presence identified HSF1 variants, leading impaired

Language: Английский

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PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1246 - 1246

Published: Jan. 31, 2025

The current opinion manuscript posits that not only Piezo2 voltage block, but also proton affinity and availability in relation to Piezo2, a mechanically gated ion channel, may count the mediation of pain its sensitivity. Moreover, this paper argues autonomously acquired channelopathy on somatosensory terminals is likely initiating peripheral impaired input source drives central sensitization spinal nociceptive neurons chronic path as being autonomous generator. In parallel, proprioception resultant progressive deficit neuromuscular junctions motoneurons might be initiated by impairment proton-based ultrafast proprioceptive feedback due disconnection through vesicular glutamate transporter 1. irreversible form channel microdamage, association with genetic predisposition and/or environmental risk factors, suggested lead motoneuron death addition loss sensation amyotrophic lateral sclerosis. Furthermore, long-range oscillatory synchronization hippocampus 2 gain further importance modulation formation path. Overall, novel, unaccounted Piezo2-initiated protonic extrafast signaling, including both rapid ones, within nervous system seems essential order maintain life. Hence, microdamage promotes neurodegeneration accelerates aging, while complete it incompatible life sustainment, proposed

Language: Английский

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Delayed-Onset Muscle Soreness Begins with a Transient Neural Switch

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2319 - 2319

Published: March 5, 2025

Unaccustomed and/or strenuous eccentric contractions are known to cause delayed-onset muscle soreness. In spite of this fact, their exact and mechanism have been unknown for more than 120 years. The exploration the diverse functionality Piezo2 ion channel, as principal proprioceptive component, its autonomously acquired channelopathy may bring light apparently simple but mysterious pain condition. Correspondingly, neurocentric non-contact acute compression axonopathy theory soreness suggests two damage phases affecting compartments, including intrafusal (within spindle) extrafusal (outside ones. secondary phase in space is relatively well explored. However, suggested primary within spindle far from being entirely known. current manuscript describes how proposed channelopathy-induced could be initiating transient neural switch unfolding This results a quantum mechanical free energy-stimulated ultrafast proton-coupled signaling rapid glutamate-based along muscle-brain axis. addition, it induces metabolic or, even importantly, an energy generation Type Ia terminals that eventually leads glutaminolysis deficit mitochondrial deficiency, not mention force switch. summary, or likely inward unidirectional proton pathway reversal between auxiliary ligands, leading channelopathy.

Language: Английский

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Delayed Onset Muscle Soreness and Critical Neural Microdamage-Derived Neuroinflammation

Biomolecules, Journal Year: 2022, Volume and Issue: 12(9), P. 1207 - 1207

Published: Aug. 31, 2022

Piezo2 transmembrane excitatory mechanosensitive ion channels were identified as the principal mechanotransduction for proprioception. Recently, it was postulated that could be acutely microdamaged on an autologous basis at proprioceptive Type Ia terminals in a cognitive demand-induced acute stress response time window when unaccustomed or strenuous eccentric contractions are executed. One consequence of this proposed transient microinjury VGLUT1/Ia synaptic disconnection motoneurons, we can learn from platinum-analogue chemotherapy. A secondary, harsher injury phase with involvement polymodal Aδ and nociceptive C-fibers follow primary impairment proprioception delayed onset muscle soreness. Repetitive reinjury these form repeated bout effects is to tertiary phase. Notably, use associated motor learning memory. The monosynaptic static firing sensory encoding affected stretch reflex immediate microdamage leading impaired proprioception, exaggerated reduced range motion. These channelopathies afferent constitute critical gateway pathophysiology Correspondingly, fatiguing contraction-based pathological hyperexcitation afferents induces reactive oxygen species production-associated neuroinflammation neuronal activation spinal cord

Language: Английский

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Miswired Proprioception in Amyotrophic Lateral Sclerosis in Relation to Pain Sensation (and in Delayed Onset Muscle Soreness)—Is Piezo2 Channelopathy a Principal Transcription Activator in Proprioceptive Terminals Besides Being the Potential Primary Damage?

Life, Journal Year: 2023, Volume and Issue: 13(3), P. 657 - 657

Published: Feb. 27, 2023

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative multisystem disease, with an unknown pathomechanism, resulting in progressive motoneuron loss. In 90-95% of cases, ALS sporadic, but close to 10% familial inherited gene mutations from family members. Recently, non-contact dying-back injury mechanism theory postulated that irreversible intrafusal proprioceptive terminal degeneration induces the non-resolving impairment circuitry, leading loss, overloading and depletion central nervous system, eventually death. The current manuscript proposes Piezo2 channelopathy this constantly activated dysregulated transcription process ALS, providing access underlying pathogenic variants letting cell-type-specific noncoding DNA become more apparent. This opinion piece genes are associated both downstream upstream, their mutations, along aging process, could explain ALS. Moreover, microinjury ion channel be primary damage or root cause death Finally, also depicts pathomechanism as why considered painless disease.

Language: Английский

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Role of proprioceptors in chronic musculoskeletal pain

Experimental Physiology, Journal Year: 2023, Volume and Issue: 109(1), P. 45 - 54

Published: July 7, 2023

Abstract Proprioceptors are non‐nociceptive low‐threshold mechanoreceptors. However, recent studies have shown that proprioceptors acid‐sensitive and express a variety of proton‐sensing ion channels receptors. Accordingly, although commonly known as mechanosensing neurons monitor muscle contraction status body position, they may role in the development pain associated with tissue acidosis. In clinical practice, proprioception training is beneficial for relief. Here we summarize current evidence to sketch different ‘non‐nociceptive pain’ focus on their acid‐sensing properties.

Language: Английский

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Likely Pathogenic Variants of Cav1.3 and Nav1.1 Encoding Genes in Amyotrophic Lateral Sclerosis Could Elucidate the Dysregulated Pain Pathways

Biomedicines, Journal Year: 2023, Volume and Issue: 11(3), P. 933 - 933

Published: March 17, 2023

Amyotrophic lateral sclerosis (ALS) is a lethal multisystem neurodegenerative disease associated with progressive loss of motor neurons, leading to death. Not only the clinical picture ALS heterogenous, but also pain sensation due different types involvement. used be considered painless disease, research has been emerging and depicting more complex representation in ALS. Pain detected even couple years before symptomatic stage ALS, referring primary muscle denervation, although secondary nociceptive causes part picture. A new non-contact dying-back injury mechanism theory recently postulated that irreversible intrafusal proprioceptive Piezo2 microinjury could damage, underlying genetic environmental risk factors. Moreover, this damage proposed dysregulate pathways spinal dorsal horn lost imbalanced subthreshold Ca2+ currents, NMDA activation L-type wide dynamic range neurons. Our investigation first show likely pathogenic variants Cav1.3 encoding CACNA1D gene may play role pathology dysregulation or sensation. Furthermore, our reanalysis shows SCN1A might contribute dysregulated Finally, absence points toward However, molecular investigations are needed identify functionally diverse features novel critical pathway.

Language: Английский

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Should We Void Lactate in the Pathophysiology of Delayed Onset Muscle Soreness? Not So Fast! Let’s See a Neurocentric View!

Metabolites, Journal Year: 2022, Volume and Issue: 12(9), P. 857 - 857

Published: Sept. 13, 2022

The pathophysiology of delayed onset muscle soreness is not entirely known. It seems to be a simple, exercise-induced pain condition, but has remained mystery for over 120 years. buildup lactic acid used blamed fatigue and soreness; however, studies in the 1980s largely refuted role lactate soreness. Regardless, this belief widely held even today, only general public, within medical scientific community as well. Current opinion highlighting lactate's soreness, if neural dimension neuro-energetics are overlooked. By doing so, have an essential initiation primary damage phase intrafusal space. Unaccustomed or strenuous eccentric contractions suggested facilitate nourishment proprioceptive sensory neurons spindle under hyperexcitation. However, excessive acidosis could eventually contribute impaired proprioception increased nociception pathological condition. Furthermore, also secondary extrafusal space, primarily by potentiating bradykinin. After all, interpretation may help us dispel 40-year-old controversy about

Language: Английский

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Influence of combined transcranial and peripheral electromagnetic stimulation on the autonomous nerve system on delayed onset muscle soreness in young athletes: a randomized clinical trial

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 10, 2025

Delayed Onset Muscle Soreness (DOMS) represents a common challenge for athletes and has been focal point of research in sports science. Eccentric exercise, known to induce DOMS, significantly impacts recovery physiological processes. Electromagnetic stimulation, both transcranial peripheral, gained attention medicine due its demonstrated benefits various conditions, offering potential as recovery-enhancing tool athletes. This study aimed evaluate the effects combined peripheral electromagnetic stimulation on autonomic nervous system response young experiencing DOMS. A randomized, double-blind was conducted with 48 divided into four groups: Control (n = 12), Peripheral Stimulation 13), Transcranial 11), Combined 12). Participants underwent an eccentric exercise session followed by their respective interventions: no group, 5 min (LTP protocol) 20 combination (30 total) group. The assessed through Heart Rate Variability (HRV) parameters measured before, immediately after, at 24 h, 72 h post-intervention. group exhibited significant improvements HRV parameters, including increased Low Frequency (LF, p < 0.001), High (HF, LF/HF power ratio (p 0.001) post-intervention compared other groups. These findings suggest that paired-associative effectively enhances regulation promotes after exercise-induced positively influences responses, accelerating without disrupting natural mechanisms. approach presents promising intervention

Language: Английский

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