SMN1型
脊髓性肌萎缩
生物
粒体自噬
线粒体
细胞生物学
品脱1
基因剔除小鼠
形状记忆合金*
骨骼肌
肌肉萎缩
内分泌学
遗传学
基因
细胞凋亡
自噬
数学
组合数学
作者
Francesco Chemello,Michela Pozzobon,Lorenza Iolanda Tsansizi,Tatiana Varanita,Ruben Quintana-Cabrera,Daniele Bonesso,Martina Piccoli,Gerolamo Lanfranchi,Marta Giacomello,Luca Scorrano,Camilla Bean
标识
DOI:10.1038/s41419-023-05573-x
摘要
Abstract The approved gene therapies for spinal muscular atrophy (SMA), caused by loss of survival motor neuron 1 (SMN1), greatly ameliorate SMA natural history but are not curative. These therapies primarily target motor neurons, but SMN1 loss has detrimental effects beyond motor neurons and especially in muscle. Here we show that SMN loss in mouse skeletal muscle leads to accumulation of dysfunctional mitochondria. Expression profiling of single myofibers from a muscle specific Smn1 knockout mouse model revealed down-regulation of mitochondrial and lysosomal genes. Albeit levels of proteins that mark mitochondria for mitophagy were increased, morphologically deranged mitochondria with impaired complex I and IV activity and respiration and that produced excess reactive oxygen species accumulated in Smn1 knockout muscles, because of the lysosomal dysfunction highlighted by the transcriptional profiling. Amniotic fluid stem cells transplantation that corrects the SMN knockout mouse myopathic phenotype restored mitochondrial morphology and expression of mitochondrial genes. Thus, targeting muscle mitochondrial dysfunction in SMA may complement the current gene therapy.
科研通智能强力驱动
Strongly Powered by AbleSci AI