Department of Biology, University of Padova, 35121, Padova, Italy.
Women's and Children's Health Department, University of Padova, 35121, Padova, Italy.
Cell Death Dis. 2023 Feb 27;14(2):162. doi: 10.1038/s41419-023-05573-x.
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.
已批准的脊髓性肌萎缩症（SMA）基因疗法，由生存运动神经元 1（SMN1）缺失引起，极大地改善了 SMA 的自然病程，但不能治愈。这些疗法主要针对运动神经元，但 SMN1 的缺失对运动神经元以外的组织，特别是肌肉，有不良影响。在这里，我们发现小鼠骨骼肌中的 SMN 缺失导致功能失调的线粒体积累。对肌肉特异性 Smn1 敲除小鼠模型的单个肌纤维进行表达谱分析显示，线粒体和溶酶体基因下调。虽然标记线粒体进行线粒体自噬的蛋白质水平增加，但形态异常的线粒体，其复合物 I 和 IV 活性和呼吸受损，并且由于转录谱突出显示的溶酶体功能障碍，产生过多的活性氧在 Smn1 敲除肌肉中积累。羊膜干细胞移植纠正了 SMN 敲除小鼠的肌病表型，恢复了线粒体形态和线粒体基因的表达。因此，针对 SMA 中的肌肉线粒体功能障碍可能是对现有基因治疗的补充。
