Characterization of SMA type II skeletal muscle from treated patients shows OXPHOS deficiency and denervation
Fiorella Carla Grandi, Stéphanie Astord, Sonia Pezet, Elèna Gidaja, Sabrina Mazzucchi, Maud Chapart, Stéphane Vasseur, Kamel Mamchaoui, Piera Smeriglio
Fiorella Carla Grandi, Stéphanie Astord, Sonia Pezet, Elèna Gidaja, Sabrina Mazzucchi, Maud Chapart, Stéphane Vasseur, Kamel Mamchaoui, Piera Smeriglio
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Research Article Genetics Muscle biology

Characterization of SMA type II skeletal muscle from treated patients shows OXPHOS deficiency and denervation

Abstract

Spinal muscular atrophy (SMA) is a recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (survival of motor neuron 1). SMA is characterized by neuromuscular symptoms and muscle weakness. Several years ago, SMA treatment underwent a radical transformation, with the approval of 3 different SMN-dependent disease-modifying therapies. This includes 2 SMN2 splicing therapies — risdiplam and nusinersen. One main challenge for type II SMA patients treated with these drugs is ongoing muscle fatigue, limited mobility, and other skeletal problems. To date, few molecular studies have been conducted on SMA patient–derived tissues after treatment, limiting our understanding of what targets remain unchanged after the spinal cord–targeted therapies are applied. Therefore, we collected paravertebral muscle from 8 type II patients undergoing spinal surgery for scoliosis and 7 controls. We used RNA-seq to characterize their transcriptional profiles and correlate these molecular changes with muscle histology. Despite the limited cohort size and heterogeneity, we observed a consistent loss of oxidative phosphorylation (OXPHOS) machinery of the mitochondria, a decrease in mitochondrial DNA copy number, and a correlation between signals of cellular stress, denervation, and increased fibrosis. This work provides new putative targets for combination therapies for type II SMA.

Authors

Fiorella Carla Grandi, Stéphanie Astord, Sonia Pezet, Elèna Gidaja, Sabrina Mazzucchi, Maud Chapart, Stéphane Vasseur, Kamel Mamchaoui, Piera Smeriglio

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Figure 2

SMA type II paravertebral muscle after treatment is characterized by abnormal myofiber size distribution.

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SMA type II paravertebral muscle after treatment is characterized by abn...
(A) H&E staining of muscle tissues from control and SMA patient samples. Representative images (3–5 images were acquired per sample) are shown for each group. Original magnification, ×200. Scale bars: 50 μm. (B) Histogram of the fiber area. The frequency distribution represents the percentage of all fibers per group that falls within the bin area. Fiber area was measured in arbitrary units. n = 6 controls and n = 5 SMA, with multiple fiber measurements per sample, taken from 1 representative image per sample. (C) The range (highest to lowest) of fiber area measurements per patient. Each data point represents 1 image of 1 patient sample (n = 6 controls, n = 5 SMA). Group averages were compared using a 2-sided Student’s t test. *P < 0.05. (D) The maximum fiber area measured for each patient from 1 representative image. Each data point represents 1 patient (n = 6 controls and n = 5 SMA). Group averages were compared using a 2-sided Student’s t test. *P < 0.05. (E) Representative cropped and enlarged myofibers from images showing myofibers with multiple internalized nuclei from the 2 patients where we observed this phenomenon. Internalized nuclei are designated by white arrows. (F and G) Quantification of single centralized (F) or multiple internalized nuclei (G) in SMA (n = 5) and controls (n = 6). Each data point represents the percentage of such nuclei in the fibers counted in 1 image from each patient sample. Group averages were compared using a 2-sided Student’s t test. NS, not significant (P > 0.05).