Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons
Abstract Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle co...
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doaj-6519b01e036441a5a70343d791779e8b2021-07-04T11:12:42ZengBMCActa Neuropathologica Communications2051-59602021-07-019111510.1186/s40478-021-01223-5Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneuronsAlba Sansa0Ivan Hidalgo1Maria P. Miralles2Sandra de la Fuente3M. Jose Perez-Garcia4Francina Munell5Rosa M. Soler6Ana Garcera7Neuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaPaediatric Neuromuscular Disorders Unit, Pediatric Neurology Group, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Research (VHIR)Paediatric Neuromuscular Disorders Unit, Pediatric Neurology Group, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Research (VHIR)Neuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaNeuronal Signaling Unit, Experimental Medicine Department, Universitat de Lleida-IRBLleidaAbstract Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. Therefore, studies evaluating atrophy mechanisms in SMA muscles will contribute to strengthening current knowledge of the pathology. Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. We analized autophagy proteins and mTOR in muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs differentiated from SMA and unaffected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a differential regulation in SMA of the autophagy process in muscle cells and MNs. Opposite changes in autophagy proteins and mTOR phosphorylation between muscle cells and neurons were observed. These differences may reflect a specific response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients.https://doi.org/10.1186/s40478-021-01223-5Spinal muscular atrophySurvival motor neuronAutophagyNeuromuscular diseaseHuman iPSCsNeurodegeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alba Sansa Ivan Hidalgo Maria P. Miralles Sandra de la Fuente M. Jose Perez-Garcia Francina Munell Rosa M. Soler Ana Garcera |
spellingShingle |
Alba Sansa Ivan Hidalgo Maria P. Miralles Sandra de la Fuente M. Jose Perez-Garcia Francina Munell Rosa M. Soler Ana Garcera Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons Acta Neuropathologica Communications Spinal muscular atrophy Survival motor neuron Autophagy Neuromuscular disease Human iPSCs Neurodegeneration |
author_facet |
Alba Sansa Ivan Hidalgo Maria P. Miralles Sandra de la Fuente M. Jose Perez-Garcia Francina Munell Rosa M. Soler Ana Garcera |
author_sort |
Alba Sansa |
title |
Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons |
title_short |
Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons |
title_full |
Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons |
title_fullStr |
Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons |
title_full_unstemmed |
Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons |
title_sort |
spinal muscular atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2021-07-01 |
description |
Abstract Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. Therefore, studies evaluating atrophy mechanisms in SMA muscles will contribute to strengthening current knowledge of the pathology. Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. We analized autophagy proteins and mTOR in muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients and in gastrocnemius muscles from a severe SMA mouse model. Human MNs differentiated from SMA and unaffected control iPSCs were also included in the analysis of the autophagy. Muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a differential regulation in SMA of the autophagy process in muscle cells and MNs. Opposite changes in autophagy proteins and mTOR phosphorylation between muscle cells and neurons were observed. These differences may reflect a specific response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients. |
topic |
Spinal muscular atrophy Survival motor neuron Autophagy Neuromuscular disease Human iPSCs Neurodegeneration |
url |
https://doi.org/10.1186/s40478-021-01223-5 |
work_keys_str_mv |
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