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A mutation in the dynein heavy chain gene compensates for energy deficit of mutant SOD1 mice and increases potentially neuroprotective IGF-1.

Fergani A, Eschbach J, Oudart H, Larmet Y, Schwalenstocker B, Ludolph AC, Loeffler JP, Dupuis L - Mol Neurodegener (2011)

Bottom Line: It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects.Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting.These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, F-67085 France. loeffler@unistra.fr.

ABSTRACT

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. ALS patients, as well as animal models such as mice overexpressing mutant SOD1s, are characterized by increased energy expenditure. In mice, this hypermetabolism leads to energy deficit and precipitates motor neuron degeneration. Recent studies have shown that mutations in the gene encoding the dynein heavy chain protein are able to extend lifespan of mutant SOD1 mice. It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects.

Results: SOD1(G93A) mice were crossbred with mice harboring the dynein mutant Cramping allele (Cra/+ mice). Dynein mutation increased adipose stores in compound transgenic mice through increasing carbohydrate oxidation and sparing lipids. Metabolic changes that occurred in double transgenic mice were accompanied by the normalization of the expression of key mRNAs in the white adipose tissue and liver. Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting. In SOD1(G93A) mice, the dynein Cra mutation led to increased expression of IGF-1 in the liver, increased systemic IGF-1 and, most importantly, to increased spinal IGF-1 levels that are potentially neuroprotective.

Conclusions: These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons.

No MeSH data available.


Related in: MedlinePlus

Dynein mutation increased adipose stores in early symptomatic SOD1(G93A) mice. A- mRNA levels of alpha subunit of the nicotinic acetylcholine receptor (AchRα) in gastrocnemius muscles of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) *P < 0.05 versus Wt. mRNA levels were standardized using 18S ribosomal RNA as a control. N = 9 mice per group. B-C- Relative weight of epididimary (EPI) and retroperitoneal (RP) white adipose tissue fat pad with regard to body weight (B). The panel C shows absolute weight (in mg) of EPI and RP in the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. N = 9 mice per group.
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Figure 1: Dynein mutation increased adipose stores in early symptomatic SOD1(G93A) mice. A- mRNA levels of alpha subunit of the nicotinic acetylcholine receptor (AchRα) in gastrocnemius muscles of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) *P < 0.05 versus Wt. mRNA levels were standardized using 18S ribosomal RNA as a control. N = 9 mice per group. B-C- Relative weight of epididimary (EPI) and retroperitoneal (RP) white adipose tissue fat pad with regard to body weight (B). The panel C shows absolute weight (in mg) of EPI and RP in the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. N = 9 mice per group.

Mentions: We hypothesized that the protection offered by dynein mutation against SOD1(G93A) neurodegeneration was linked to a compensation of the energy deficit of SOD1(G93A) mice. To test this hypothesis, we crossbred SOD1(G93A) mice with Cra/+ mice and studied the energetic physiology of compound heterozygotes before any obvious motor symptoms. At 16 weeks of age, SOD1(G93A) nor Cra/SOD1(G93A) mice did not show obvious clinical signs such as gait impairment but both groups of SOD1(G93A) mice were lighter than wild type littermates. Body weight deficit of Cra/SOD1(G93A) mice was less than SOD1(G93A) mice (not shown) as previously shown [7] and both groups displayed similar upregulation of the denervation marker AchRα in the gastrocnemius muscle compared to non-SOD1(G93A) animals (Figure 1A). This early symptomatic age was selected for further studies. Both groups of SOD1(G93A) mice showed decreased weights of epididymary and retroperitoneal fat pads, but Cra/SOD1(G93A) fat pads were larger than that of SOD1(G93A) mice (Figure 1B-C). This was not due to increased food intake since all groups displayed similar food intake (data not shown). In all, these results demonstrate that the Cramping mutation in the dynein heavy chain gene compensated partially for SOD1(G93A) energy deficit in early symptomatic animals.


A mutation in the dynein heavy chain gene compensates for energy deficit of mutant SOD1 mice and increases potentially neuroprotective IGF-1.

Fergani A, Eschbach J, Oudart H, Larmet Y, Schwalenstocker B, Ludolph AC, Loeffler JP, Dupuis L - Mol Neurodegener (2011)

Dynein mutation increased adipose stores in early symptomatic SOD1(G93A) mice. A- mRNA levels of alpha subunit of the nicotinic acetylcholine receptor (AchRα) in gastrocnemius muscles of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) *P < 0.05 versus Wt. mRNA levels were standardized using 18S ribosomal RNA as a control. N = 9 mice per group. B-C- Relative weight of epididimary (EPI) and retroperitoneal (RP) white adipose tissue fat pad with regard to body weight (B). The panel C shows absolute weight (in mg) of EPI and RP in the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. N = 9 mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3111394&req=5

Figure 1: Dynein mutation increased adipose stores in early symptomatic SOD1(G93A) mice. A- mRNA levels of alpha subunit of the nicotinic acetylcholine receptor (AchRα) in gastrocnemius muscles of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) *P < 0.05 versus Wt. mRNA levels were standardized using 18S ribosomal RNA as a control. N = 9 mice per group. B-C- Relative weight of epididimary (EPI) and retroperitoneal (RP) white adipose tissue fat pad with regard to body weight (B). The panel C shows absolute weight (in mg) of EPI and RP in the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. N = 9 mice per group.
Mentions: We hypothesized that the protection offered by dynein mutation against SOD1(G93A) neurodegeneration was linked to a compensation of the energy deficit of SOD1(G93A) mice. To test this hypothesis, we crossbred SOD1(G93A) mice with Cra/+ mice and studied the energetic physiology of compound heterozygotes before any obvious motor symptoms. At 16 weeks of age, SOD1(G93A) nor Cra/SOD1(G93A) mice did not show obvious clinical signs such as gait impairment but both groups of SOD1(G93A) mice were lighter than wild type littermates. Body weight deficit of Cra/SOD1(G93A) mice was less than SOD1(G93A) mice (not shown) as previously shown [7] and both groups displayed similar upregulation of the denervation marker AchRα in the gastrocnemius muscle compared to non-SOD1(G93A) animals (Figure 1A). This early symptomatic age was selected for further studies. Both groups of SOD1(G93A) mice showed decreased weights of epididymary and retroperitoneal fat pads, but Cra/SOD1(G93A) fat pads were larger than that of SOD1(G93A) mice (Figure 1B-C). This was not due to increased food intake since all groups displayed similar food intake (data not shown). In all, these results demonstrate that the Cramping mutation in the dynein heavy chain gene compensated partially for SOD1(G93A) energy deficit in early symptomatic animals.

Bottom Line: It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects.Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting.These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons.

View Article: PubMed Central - HTML - PubMed

Affiliation: Inserm U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg, F-67085 France. loeffler@unistra.fr.

ABSTRACT

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. ALS patients, as well as animal models such as mice overexpressing mutant SOD1s, are characterized by increased energy expenditure. In mice, this hypermetabolism leads to energy deficit and precipitates motor neuron degeneration. Recent studies have shown that mutations in the gene encoding the dynein heavy chain protein are able to extend lifespan of mutant SOD1 mice. It remains unknown whether the protection offered by these dynein mutations relies on a compensation of energy metabolism defects.

Results: SOD1(G93A) mice were crossbred with mice harboring the dynein mutant Cramping allele (Cra/+ mice). Dynein mutation increased adipose stores in compound transgenic mice through increasing carbohydrate oxidation and sparing lipids. Metabolic changes that occurred in double transgenic mice were accompanied by the normalization of the expression of key mRNAs in the white adipose tissue and liver. Furthermore, Dynein Cra mutation rescued decreased post-prandial plasma triglycerides and decreased non esterified fatty acids upon fasting. In SOD1(G93A) mice, the dynein Cra mutation led to increased expression of IGF-1 in the liver, increased systemic IGF-1 and, most importantly, to increased spinal IGF-1 levels that are potentially neuroprotective.

Conclusions: These findings suggest that the protection against SOD1(G93A) offered by the Cramping mutation in the dynein gene is, at least partially, mediated by a reversal in energy deficit and increased IGF-1 availability to motor neurons.

No MeSH data available.


Related in: MedlinePlus