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1.
Skelet Muscle ; 14(1): 11, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38769542

RESUMO

BACKGROUND: Myotonic Dystrophy type I (DM1) is the most common muscular dystrophy in adults. Previous reports have highlighted that neuromuscular junctions (NMJs) deteriorate in skeletal muscle from DM1 patients and mouse models thereof. However, the underlying pathomechanisms and their contribution to muscle dysfunction remain unknown. METHODS: We compared changes in NMJs and activity-dependent signalling pathways in HSALR and Mbnl1ΔE3/ΔE3 mice, two established mouse models of DM1. RESULTS: Muscle from DM1 mouse models showed major deregulation of calcium/calmodulin-dependent protein kinases II (CaMKIIs), which are key activity sensors regulating synaptic gene expression and acetylcholine receptor (AChR) recycling at the NMJ. Both mouse models exhibited increased fragmentation of the endplate, which preceded muscle degeneration. Endplate fragmentation was not accompanied by changes in AChR turnover at the NMJ. However, the expression of synaptic genes was up-regulated in mutant innervated muscle, together with an abnormal accumulation of histone deacetylase 4 (HDAC4), a known target of CaMKII. Interestingly, denervation-induced increase in synaptic gene expression and AChR turnover was hampered in DM1 muscle. Importantly, CaMKIIß/ßM overexpression normalized endplate fragmentation and synaptic gene expression in innervated Mbnl1ΔE3/ΔE3 muscle, but it did not restore denervation-induced synaptic gene up-regulation. CONCLUSIONS: Our results indicate that CaMKIIß-dependent and -independent mechanisms perturb synaptic gene regulation and muscle response to denervation in DM1 mouse models. Changes in these signalling pathways may contribute to NMJ destabilization and muscle dysfunction in DM1 patients.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Modelos Animais de Doenças , Músculo Esquelético , Distrofia Miotônica , Junção Neuromuscular , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Distrofia Miotônica/fisiopatologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Junção Neuromuscular/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/inervação , Músculo Esquelético/patologia , Camundongos , Humanos , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/genética , Masculino , Camundongos Endogâmicos C57BL
2.
Nat Commun ; 12(1): 2438, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33903596

RESUMO

Cortical and limbic brain areas are regarded as centres for learning. However, how thalamic sensory relays participate in plasticity upon associative learning, yet support stable long-term sensory coding remains unknown. Using a miniature microscope imaging approach, we monitor the activity of populations of auditory thalamus (medial geniculate body) neurons in freely moving mice upon fear conditioning. We find that single cells exhibit mixed selectivity and heterogeneous plasticity patterns to auditory and aversive stimuli upon learning, which is conserved in amygdala-projecting medial geniculate body neurons. Activity in auditory thalamus to amygdala-projecting neurons stabilizes single cell plasticity in the total medial geniculate body population and is necessary for fear memory consolidation. In contrast to individual cells, population level encoding of auditory stimuli remained stable across days. Our data identifies auditory thalamus as a site for complex neuronal plasticity in fear learning upstream of the amygdala that is in an ideal position to drive plasticity in cortical and limbic brain areas. These findings suggest that medial geniculate body's role goes beyond a sole relay function by balancing experience-dependent, diverse single cell plasticity with consistent ensemble level representations of the sensory environment to support stable auditory perception with minimal affective bias.


Assuntos
Vias Auditivas/fisiologia , Plasticidade Celular/fisiologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Tálamo/fisiologia , Estimulação Acústica , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Percepção Auditiva/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Corpos Geniculados/citologia , Corpos Geniculados/fisiologia , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Tálamo/citologia
3.
Nat Commun ; 10(1): 3187, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320633

RESUMO

Loss of innervation of skeletal muscle is a determinant event in several muscle diseases. Although several effectors have been identified, the pathways controlling the integrated muscle response to denervation remain largely unknown. Here, we demonstrate that PKB/Akt and mTORC1 play important roles in regulating muscle homeostasis and maintaining neuromuscular endplates after nerve injury. To allow dynamic changes in autophagy, mTORC1 activation must be tightly balanced following denervation. Acutely activating or inhibiting mTORC1 impairs autophagy regulation and alters homeostasis in denervated muscle. Importantly, PKB/Akt inhibition, conferred by sustained mTORC1 activation, abrogates denervation-induced synaptic remodeling and causes neuromuscular endplate degeneration. We establish that PKB/Akt activation promotes the nuclear import of HDAC4 and is thereby required for epigenetic changes and synaptic gene up-regulation upon denervation. Hence, our study unveils yet-unknown functions of PKB/Akt-mTORC1 signaling in the muscle response to nerve injury, with important implications for neuromuscular integrity in various pathological conditions.


Assuntos
Autofagia/fisiologia , Histona Desacetilases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Denervação Muscular , Músculo Esquelético/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Linhagem Celular , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Placa Motora/patologia , Atrofia Muscular/patologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética
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