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Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

Sintusek P, Catapano F, Angkathunkayul N, Marrosu E, Parson SH, Morgan JE, Muntoni F, Zhou H - PLoS ONE (2016)

Bottom Line: We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression.Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice.We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON.

View Article: PubMed Central - PubMed

Affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.

ABSTRACT
Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

No MeSH data available.


Related in: MedlinePlus

Gross anatomical features of the bowel in SMA, control and PMO25 treated SMA mice.(A) Images of the whole bowel from 10 day old SMA (N = 3), control (N = 3) and PMO25 treated SMA mice (N = 3). Specimens were pinned in order to display the whole bowel length. Arrows indicate proximal duodenum and arrowheads identify the cecum. (B) Representative image of SMA and PMO25 treated SMA mice at PND10. (C) SMA mice had the shortest whole bowel length compared to control and PMO25 treated mice. (P< 0.0001 vs control and vs SMA+PMO25. N = 6–7). (D) The mean small bowel length was significantly lower in SMA mice than in control and treated mice (P< 0.0001 vs control and vs SMA+PMO25 in small bowel. N = 3–4). (E) SMA mice displayed the lowest body weight compared to control and PMO25 treated mice. (P< 0.0001 vs control and P<0.0001 vs SMA+PMO25. N = 3–4). The relative total intestine length to body weight (F) and relative small intestinal length to body weight (G) in SMA mice were significantly higher than those in control and PMO25 treated mice (P<0.0001 N = 3–4). ***P < 0.001, *P<0.05.
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pone.0155032.g001: Gross anatomical features of the bowel in SMA, control and PMO25 treated SMA mice.(A) Images of the whole bowel from 10 day old SMA (N = 3), control (N = 3) and PMO25 treated SMA mice (N = 3). Specimens were pinned in order to display the whole bowel length. Arrows indicate proximal duodenum and arrowheads identify the cecum. (B) Representative image of SMA and PMO25 treated SMA mice at PND10. (C) SMA mice had the shortest whole bowel length compared to control and PMO25 treated mice. (P< 0.0001 vs control and vs SMA+PMO25. N = 6–7). (D) The mean small bowel length was significantly lower in SMA mice than in control and treated mice (P< 0.0001 vs control and vs SMA+PMO25 in small bowel. N = 3–4). (E) SMA mice displayed the lowest body weight compared to control and PMO25 treated mice. (P< 0.0001 vs control and P<0.0001 vs SMA+PMO25. N = 3–4). The relative total intestine length to body weight (F) and relative small intestinal length to body weight (G) in SMA mice were significantly higher than those in control and PMO25 treated mice (P<0.0001 N = 3–4). ***P < 0.001, *P<0.05.

Mentions: The severe SMA mice have extremely shortened lifespan and distinctly small body size. These phenotypes can be successfully rescued by systemic morpholino antisense oligomer treatment [10, 30]. To determine the general condition of the GI system in the severe SMA mice and the response to systemic PMO25 treatment, we measured the length of intestine and the body weight (Fig 1A and 1B). There was a significant reduction in the length (mm) of the intestine in SMA mice (total length: 99.71 ± 5.63 N = 7; small intestine: 91.25 ± 3.14 N = 4) compared to control mice (total length: 208.7 ± 9.28 N = 6; small intestine: 186.3 ± 4.33 N = 3; P<0.0001) (Fig 1A, 1C and 1D). There was also a significant reduction in body weight (gram) in SMA mice (1.75 ± 0.08 N = 4) compared to control mice (5.52 ± 0.07 N = 3; P<0.0001) (Fig 1E). However, the relative length of intestine to body weight (mm/g) in SMA mice (relative total intestinal length: 63.37 ± 1.17 N = 4; relative small intestinal length: 52.19 ± 0.81 N = 4) was significantly higher than those in control mice (relative total intestinal length: 40.86 ± 1.22 N = 3, P<0.0001; relative small intestinal length: 33.74 ± 1.05 N = 3, P<0.0001) (Fig 1F and 1G). This suggests that SMA mice, though very small, had disproportionately long intestines compared to control. After PMO25 treatment, both the body weight (4.06 ± 0.25 N = 4; P<0.001 vs SMA) and bowel length (total length: 191.0 ± 4.03 N = 7; small intestine: 161.0 ± 5.75 N = 4; P<0.001 vs SMA) were significantly restored to near-normal levels (Fig 1C, 1D and 1E). PMO25 treated mice also showed a significant reduction in the relative length of the full (48.07 ± 2.04 N = 4; P = 0.0006 vs SMA) and small intestine (39.91 ± 1.63 N = 4; P = 0.0005 vs SMA) (Fig 1F and 1G). This indicates that AON treatment has restored body weight and relative length of the intestines to near-normal values.


Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment.

Sintusek P, Catapano F, Angkathunkayul N, Marrosu E, Parson SH, Morgan JE, Muntoni F, Zhou H - PLoS ONE (2016)

Gross anatomical features of the bowel in SMA, control and PMO25 treated SMA mice.(A) Images of the whole bowel from 10 day old SMA (N = 3), control (N = 3) and PMO25 treated SMA mice (N = 3). Specimens were pinned in order to display the whole bowel length. Arrows indicate proximal duodenum and arrowheads identify the cecum. (B) Representative image of SMA and PMO25 treated SMA mice at PND10. (C) SMA mice had the shortest whole bowel length compared to control and PMO25 treated mice. (P< 0.0001 vs control and vs SMA+PMO25. N = 6–7). (D) The mean small bowel length was significantly lower in SMA mice than in control and treated mice (P< 0.0001 vs control and vs SMA+PMO25 in small bowel. N = 3–4). (E) SMA mice displayed the lowest body weight compared to control and PMO25 treated mice. (P< 0.0001 vs control and P<0.0001 vs SMA+PMO25. N = 3–4). The relative total intestine length to body weight (F) and relative small intestinal length to body weight (G) in SMA mice were significantly higher than those in control and PMO25 treated mice (P<0.0001 N = 3–4). ***P < 0.001, *P<0.05.
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pone.0155032.g001: Gross anatomical features of the bowel in SMA, control and PMO25 treated SMA mice.(A) Images of the whole bowel from 10 day old SMA (N = 3), control (N = 3) and PMO25 treated SMA mice (N = 3). Specimens were pinned in order to display the whole bowel length. Arrows indicate proximal duodenum and arrowheads identify the cecum. (B) Representative image of SMA and PMO25 treated SMA mice at PND10. (C) SMA mice had the shortest whole bowel length compared to control and PMO25 treated mice. (P< 0.0001 vs control and vs SMA+PMO25. N = 6–7). (D) The mean small bowel length was significantly lower in SMA mice than in control and treated mice (P< 0.0001 vs control and vs SMA+PMO25 in small bowel. N = 3–4). (E) SMA mice displayed the lowest body weight compared to control and PMO25 treated mice. (P< 0.0001 vs control and P<0.0001 vs SMA+PMO25. N = 3–4). The relative total intestine length to body weight (F) and relative small intestinal length to body weight (G) in SMA mice were significantly higher than those in control and PMO25 treated mice (P<0.0001 N = 3–4). ***P < 0.001, *P<0.05.
Mentions: The severe SMA mice have extremely shortened lifespan and distinctly small body size. These phenotypes can be successfully rescued by systemic morpholino antisense oligomer treatment [10, 30]. To determine the general condition of the GI system in the severe SMA mice and the response to systemic PMO25 treatment, we measured the length of intestine and the body weight (Fig 1A and 1B). There was a significant reduction in the length (mm) of the intestine in SMA mice (total length: 99.71 ± 5.63 N = 7; small intestine: 91.25 ± 3.14 N = 4) compared to control mice (total length: 208.7 ± 9.28 N = 6; small intestine: 186.3 ± 4.33 N = 3; P<0.0001) (Fig 1A, 1C and 1D). There was also a significant reduction in body weight (gram) in SMA mice (1.75 ± 0.08 N = 4) compared to control mice (5.52 ± 0.07 N = 3; P<0.0001) (Fig 1E). However, the relative length of intestine to body weight (mm/g) in SMA mice (relative total intestinal length: 63.37 ± 1.17 N = 4; relative small intestinal length: 52.19 ± 0.81 N = 4) was significantly higher than those in control mice (relative total intestinal length: 40.86 ± 1.22 N = 3, P<0.0001; relative small intestinal length: 33.74 ± 1.05 N = 3, P<0.0001) (Fig 1F and 1G). This suggests that SMA mice, though very small, had disproportionately long intestines compared to control. After PMO25 treatment, both the body weight (4.06 ± 0.25 N = 4; P<0.001 vs SMA) and bowel length (total length: 191.0 ± 4.03 N = 7; small intestine: 161.0 ± 5.75 N = 4; P<0.001 vs SMA) were significantly restored to near-normal levels (Fig 1C, 1D and 1E). PMO25 treated mice also showed a significant reduction in the relative length of the full (48.07 ± 2.04 N = 4; P = 0.0006 vs SMA) and small intestine (39.91 ± 1.63 N = 4; P = 0.0005 vs SMA) (Fig 1F and 1G). This indicates that AON treatment has restored body weight and relative length of the intestines to near-normal values.

Bottom Line: We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression.Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice.We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON.

View Article: PubMed Central - PubMed

Affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health, University College London, London, United Kingdom.

ABSTRACT
Gastrointestinal (GI) defects, including gastroesophageal reflux, constipation and delayed gastric emptying, are common in patients with spinal muscular atrophy (SMA). Similar GI dysmotility has been identified in mouse models with survival of motor neuron (SMN) protein deficiency. We previously described vascular defects in skeletal muscle and spinal cord of SMA mice and we hypothesized that similar defects could be involved in the GI pathology observed in these mice. We therefore investigated the gross anatomical structure, enteric vasculature and neurons in the small intestine in a severe mouse model of SMA. We also assessed the therapeutic response of GI histopathology to systemic administration of morpholino antisense oligonucleotide (AON) designed to increase SMN protein expression. Significant anatomical and histopathological abnormalities, with striking reduction of vascular density, overabundance of enteric neurons and increased macrophage infiltration, were detected in the small intestine in SMA mice. After systemic AON treatment in neonatal mice, all the abnormalities observed were significantly restored to near-normal levels. We conclude that the observed GI histopathological phenotypes and functional defects observed in these SMA mice are strongly linked to SMN deficiency which can be rescued by systemic administration of AON. This study on the histopathological changes in the gastrointestinal system in severe SMA mice provides further indication of the complex role that SMN plays in multiple tissues and suggests that at least in SMA mice restoration of SMN production in peripheral tissues is essential for optimal outcome.

No MeSH data available.


Related in: MedlinePlus