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1.
J Neurophysiol ; 131(5): 789-796, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38353653

RESUMO

Movement-evoked pain is an understudied manifestation of musculoskeletal conditions that contributes to disability, yet little is known about how the neuromuscular system responds to movement-evoked pain. The present study examined whether movement-evoked pain impacts force production, electromyographic (EMG) muscle activity, and the rate of force development (RFD) during submaximal muscle contractions. Fifteen healthy adults (9 males; age = 30.3 ± 10.2 yr, range = 22-59 yr) performed submaximal isometric first finger abduction contractions without pain (baseline) and with movement-evoked pain induced by laser stimulation to the dorsum of the hand. Normalized force (% maximal voluntary contraction) and RFD decreased by 11% (P < 0.001) and 15% (P = 0.003), respectively, with movement-evoked pain, without any change in normalized peak EMG (P = 0.77). Early contractile RFD, force impulse, and corresponding EMG amplitude computed within time segments of 50, 100, 150, and 200 ms relative to the onset of movement were also unaffected by movement-evoked pain (P > 0.05). Our results demonstrate that movement-evoked pain impairs peak characteristics and not early measures of submaximal force production and RFD, without affecting EMG activity (peak and early). Possible explanations for the stability in EMG with reduced force include antagonist coactivation and a reorganization of motoneuronal activation strategy, which is discussed here.NEW & NOTEWORTHY We provide neurophysiological evidence to indicate that peak force and rate of force development are reduced by movement-evoked pain despite a lack of change in EMG and early rapid force development in the first dorsal interosseous muscle. Additional evidence suggests that these findings may coexist with a reorganization in motoneuronal activation strategy.


Assuntos
Eletromiografia , Músculo Esquelético , Humanos , Masculino , Adulto , Feminino , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Pessoa de Meia-Idade , Adulto Jovem , Movimento/fisiologia , Dor/fisiopatologia , Contração Isométrica/fisiologia , Contração Muscular/fisiologia
2.
Neuron ; 112(3): 362-383.e15, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38016472

RESUMO

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a deep learning method to predict disease state accurately and identified specific features that enable accurate distinction of wild-type and SCA1 cells. Together, this work reveals new roles for diverse cerebellar cell types in SCA1 and provides a generalizable analysis framework for studying neurodegeneration.


Assuntos
Ataxias Espinocerebelares , Animais , Camundongos , Humanos , Ataxina-1/genética , Camundongos Transgênicos , Ataxias Espinocerebelares/metabolismo , Cerebelo/metabolismo , Células de Purkinje/metabolismo , Modelos Animais de Doenças
3.
J Clin Invest ; 133(16)2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37384409

RESUMO

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP, encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43-positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS-causing (fALS-causing) mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer's disease, and Parkinson's disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a function of nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Lisossomos/metabolismo , Doenças Neurodegenerativas/genética , Humanos
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