SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis

Ikenaka, Akihiro; Kitagawa, Yohko; Yoshida, Michiko; Lin, Chwan-Fwu; Niwa, Akira; Nakahata, Tatsutoshi; Saito, Megumu K.

doi:10.26508/lsa.202201457

Cited by 15 publications

(10 citation statements)

References 59 publications

(104 reference statements)

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“…Perhaps the best established of these is the role of miR-206 in skeletal muscle maturation and specifically mitochondrial health 80,81 . Furthermore, many studies in SMA have highlighted the essential role of alterations of miRNAs to the SMA phenotype, and these miRNA have also been proposed as biomarkers of Nusinersen response and disease progression 78,82–87 . If changes in miRNA expression observed in SMA are a direct or indirect consequence remains to be determined, although one study suggests that SMN is involved in the direct transcription of some microRNAs 82 .…”

Section: Resultsmentioning

confidence: 99%

“…This is in-line with previous reports that metabolic maturation in muscle stem cells in partially achieved by miR-1 mediated inhibition of the Dlk-1-Dio3 locus, which contains miRs that repress mitochondrial gene expression 88 . One recent study found that SMN, in combination with MYOD, can regulate the expression of miRNAs that are related to mitochondrial gene regulation, including miR-1 82 . However, we observed this decrease despite detecting similar levels of SMN protein ( Figure 1 C ), suggesting additional levels of regulation.…”

Section: Resultsmentioning

confidence: 99%

“…Similar results were obtained from SMA motor neurons 104,105 , where the authors also noted that these complex I deficiencies can cause the accumulation of ROS, which has cascading effects on other protein homeostatic processes 105 . In the in vitro model system C2C12, SMN has been proposed to target, in combination with MYOD, two key miRNAs for mitochondrial health: miR-1 and miR-206 82 . Similar alterations in the muscle’s metabolic processes, measured by MRI after muscle stress tests, were obtained in Type III and IV SMA patients 106 .…”

Section: Discussionmentioning

confidence: 99%

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SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Grandi,

Astord,

Gidaja

et al. 2024

Preprint

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Spinal muscular atrophy (SMA) is a rare autosomal recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (Survival of Spinal Motor Neuron 1). SMA is classically characterized by neuromuscular symptoms, including muscular atrophy, weakness of the proximal muscles, especially those of the lower extremities, and hypotonia. Although originally thought of as a purely motor neuron disease, current research has shown that most, if not all, tissues are affected, including the muscle. Until recently, muscle problems in SMA were predominantly considered a consequence of denervation due to the motor neuron death. However, recent work using muscle specific mouse models of SMN loss, as well as skeletal stem cell specific models have shown that there are tissue specific problems in muscle due to SMN deficiency. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies, Risdiplam and Nusinersen, which can be administered by Type II patients that have symptom onset later in age. One main challenge for Type II SMA patients treated with Risdiplam and Nusinersen is ongoing muscle fatigue, limited mobility, and other skeletal problems, including hip dysplasia and scoliosis. To date, few molecular studies have been conducted on SMA patient derived tissues after treatment, limiting our understanding how different organ systems react to the therapies, and what additional combination therapies may be beneficial. With this goal in mind, we collected paravertebral muscle from the surgical discard in a cohort of 8 SMA Type II patients undergoing spinal surgery for scoliosis, as well as 7 non SMA controls with scoliosis and used RNA sequencing to characterize their molecular profiles. We observed that despite a restoration of the SMN mRNA and protein levels in these patients, at levels at or above the controls, a subset of patients continued to have alterations in mitochondrial metabolism and other markers of cellular stress.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Grandi,

Astord,

Gidaja

et al. 2024

Preprint

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“…The myotube formation ability of C2C12 cells has been used to evaluate the repair and regeneration of muscle after injury [ 4 ]. Numerous studies have evaluated the regulation of muscle atrophy and damage by using differentiated C2C12 myotubes [ 47 , 48 ], and C2C12 myotube diameter was used to assess the myotube formation ability of C2C12 cells [ 4 ]. Notably, C2C12 myoblast cells can differentiate into myotubes and have been used as an in vitro model of skeletal muscle differentiation [ 45 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Enrichment of miR-17-5p enhances the protective effects of EPC-EXs on vascular and skeletal muscle injury in a diabetic hind limb ischemia model

Pan

et al. 2023

Biol Res

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Background/aims Diabetes mellitus (DM) is highly susceptible to diabetic hind limb ischemia (DHI). MicroRNA (MiR)-17-5p is downregulated in DM and plays a key role in vascular protection. Endothelial progenitor cell (EPC)-released exosomes (EPC-EXs) contribute to vascular protection and ischemic tissue repair by transferring their contained miRs to target cells. Here, we investigated whether miR-17-5p-enriched EPC-EXs (EPC-EXsmiR-17-5p) had conspicuous effects on protecting vascular and skeletal muscle in DHI in vitro and in vivo. Methods EPCs transfected with scrambled control or miR-17-5p mimics were used to generate EPC-EXs and EPC-EXsmiR-17-5p. Db/db mice were subjected to hind limb ischemia. After the surgery, EPC-EXs and EPC-EXsmiR-17-5p were injected into the gastrocnemius muscle of the hind limb once every 7 days for 3 weeks. Blood flow, microvessel density, capillary angiogenesis, gastrocnemius muscle weight, structure integrity, and apoptosis in the hind limb were assessed. Vascular endothelial cells (ECs) and myoblast cells (C2C12 cells) were subjected to hypoxia plus high glucose (HG) and cocultured with EPC-EXs and EPC-EXsmiR-17-5p. A bioinformatics assay was used to analyze the potential target gene of miR-17-5p, the levels of SPRED1, PI3K, phosphorylated Akt, cleaved caspase-9 and cleaved caspase-3 were measured, and a PI3K inhibitor (LY294002) was used for pathway analysis. Results In the DHI mouse model, miR-17-5p was markedly decreased in hind limb vessels and muscle tissues, and infusion of EPC-EXsmiR-17-5p was more effective than EPC-EXs in increasing miR-17-5p levels, blood flow, microvessel density, and capillary angiogenesis, as well as in promoting muscle weight, force production and structural integrity while reducing apoptosis in gastrocnemius muscle. In Hypoxia plus HG-injured ECs and C2C12 cells, we found that EPC-EXsmiR-17-5p could deliver their carried miR-17-5p into target ECs and C2C12 cells and subsequently downregulate the target protein SPRED1 while increasing the levels of PI3K and phosphorylated Akt. EPC-EXsmiR-17-5p were more effective than EPC-EXs in decreasing apoptosis and necrosis while increasing viability, migration, and tube formation in Hypoxia plus HG-injured ECs and in decreasing apoptosis while increasing viability and myotube formation in C2C12 cells. These effects of EPC-EXsmiR-17-5p could be abolished by a PI3K inhibitor (LY294002). Conclusion Our results suggest that miR-17-5p promotes the beneficial effects of EPC-EXs on DHI by protecting vascular ECs and muscle cell functions.

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“…Although a disease phenotype was not immediately obvious, persistent low levels of the protein eventually resulted in muscle fiber defects, NMJ abnormalities, poor motor performance, and premature death. Recently, Ikenaka et al found that the down-regulation of SMN causes mitochondrial dysfunction and subsequent cell death in in vitro models of skeletal myogenesis with both a murine C2C12 cell line and human induced pluripotent stem cells [63]. They reported that during myogenesis, a decrease in SMN protein may reduce the production of myoblast determination protein 1 (MYOD1), microRNA (miR)-1 and miR-206, resulting in mitochondrial dysfunction.…”

Section: Smn Protein In Tissues Associated With Sma Pathologymentioning

confidence: 99%

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

Nishio

Niba

Saitô

et al. 2023

IJMS

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Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance. The first cases of SMA were reported by Werdnig in 1891. Although the phenotypic variation of SMA led to controversy regarding the clinical entity of the disease, the genetic homogeneity of SMA was proved in 1990. Five years later, in 1995, the gene responsible for SMA, SMN1, was identified. Genetic testing of SMN1 has enabled precise epidemiological studies, revealing that SMA occurs in 1 of 10,000 to 20,000 live births and that more than 95% of affected patients are homozygous for SMN1 deletion. In 2016, nusinersen was the first drug approved for treatment of SMA in the United States. Two other drugs were subsequently approved: onasemnogene abeparvovec and risdiplam. Clinical trials with these drugs targeting patients with pre-symptomatic SMA (those who were diagnosed by genetic testing but showed no symptoms) revealed that such patients could achieve the milestones of independent sitting and/or walking. Following the great success of these trials, population-based newborn screening programs for SMA (more precisely, SMN1-deleted SMA) have been increasingly implemented worldwide. Early detection by newborn screening and early treatment with new drugs are expected to soon become the standards in the field of SMA.

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SMN promotes mitochondrial metabolic maturation during myogenesis by regulating the MYOD-miRNA axis

Cited by 15 publications

References 59 publications

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Enrichment of miR-17-5p enhances the protective effects of EPC-EXs on vascular and skeletal muscle injury in a diabetic hind limb ischemia model

Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

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