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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 does not decrease global hypermetabolism but shifts energy metabolism of SOD1(G93A) mice towards carbohydrate use. A- Total (left panel) and resting (right panel) energy expenditure 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. Note that SOD1(G93A) mice are hypermetabolic and that the dynein mutant genotype has no effect on this hypermetabolism. N = 9 mice per group. B- Energy expenditure of the same mice than in A as a function of time. Mice bearing a Cra dynein mutation are denoted by empty symbols, and their corresponding controls by a filled symbol. Mice bearing a SOD1(G93A) (SOD1m) transgene are labeled by a squared symbol and their controls by a circle. Note that in the diurnal period, there are no differences between +/+ and Cra/+ mice but that the presence of a SOD1(G93A) transgene increases energy expenditure. On the contrary, during nocturnal activity period, the presence of either Cra/+ mutation or SOD1(G93A) transgene increases energy expenditure. N = 9 mice per group. C-D- Respiratory quotient of the same mice than in A. The four groups of mice are shown in two graphs for clarity reasons. Mice non transgenic for SOD1(G93A) (SOD1m) are shown in panel C (filled symbols, +/+; empty symbols, Cra/+). Mice transgenic for SOD1(G93A) are shown in panel D (filled symbols, +/+; empty symbols, Cra/+). Note that the presence of a dynein mutation increases respiratory quotient in otherwise wild type mice, and even more potently in SOD1(G93A) mice.
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Figure 2: Dynein mutation does not decrease global hypermetabolism but shifts energy metabolism of SOD1(G93A) mice towards carbohydrate use. A- Total (left panel) and resting (right panel) energy expenditure 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. Note that SOD1(G93A) mice are hypermetabolic and that the dynein mutant genotype has no effect on this hypermetabolism. N = 9 mice per group. B- Energy expenditure of the same mice than in A as a function of time. Mice bearing a Cra dynein mutation are denoted by empty symbols, and their corresponding controls by a filled symbol. Mice bearing a SOD1(G93A) (SOD1m) transgene are labeled by a squared symbol and their controls by a circle. Note that in the diurnal period, there are no differences between +/+ and Cra/+ mice but that the presence of a SOD1(G93A) transgene increases energy expenditure. On the contrary, during nocturnal activity period, the presence of either Cra/+ mutation or SOD1(G93A) transgene increases energy expenditure. N = 9 mice per group. C-D- Respiratory quotient of the same mice than in A. The four groups of mice are shown in two graphs for clarity reasons. Mice non transgenic for SOD1(G93A) (SOD1m) are shown in panel C (filled symbols, +/+; empty symbols, Cra/+). Mice transgenic for SOD1(G93A) are shown in panel D (filled symbols, +/+; empty symbols, Cra/+). Note that the presence of a dynein mutation increases respiratory quotient in otherwise wild type mice, and even more potently in SOD1(G93A) mice.

Mentions: We next determined whether the Cramping dynein mutation compensated for energy deficit through decreased SOD1(G93A) linked hypermetabolism. For this, we measured energy expenditure of the four groups of mice. As previously shown [3], SOD1(G93A) animals had a 15-20% increase in resting energy expenditure (Figure 2A), and this hypermetabolism was unchanged by Cramping dynein mutation. Furthermore, SOD1(G93A) associated increased total energy expenditure was also unchanged (Figure 2A) suggesting that the compensation in energy deficit was not provided by, for instance, decreased activity. Thus, the protective potential of Cramping dynein mutation was independent of a direct modulation of global hypermetabolism. Closer examination of indirect calorimetry results revealed however that oxygen consumption of SOD1(G93A) and Cra/SOD1(G93A) but also Cra/+ mice were increased during the nocturnal period as compared with +/+ littermates (Figure 2B). The respiratory quotient of Cra/+ and Cra/SOD1(G93A) mice was higher than that of +/+ and SOD1(G93A) mice at the same period (Figure 2C-D). Since oxidation of carbohydrates leads to a respiratory quotient of 1, while oxidation of lipids leads to a respiratory quotient of 0.7 [17], these results show that the dynein mutation leads to a shift in nutrient use during activity towards preferential carbohydrate oxidation, and thus sparing of lipids and increased fat pad weights.


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 does not decrease global hypermetabolism but shifts energy metabolism of SOD1(G93A) mice towards carbohydrate use. A- Total (left panel) and resting (right panel) energy expenditure 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. Note that SOD1(G93A) mice are hypermetabolic and that the dynein mutant genotype has no effect on this hypermetabolism. N = 9 mice per group. B- Energy expenditure of the same mice than in A as a function of time. Mice bearing a Cra dynein mutation are denoted by empty symbols, and their corresponding controls by a filled symbol. Mice bearing a SOD1(G93A) (SOD1m) transgene are labeled by a squared symbol and their controls by a circle. Note that in the diurnal period, there are no differences between +/+ and Cra/+ mice but that the presence of a SOD1(G93A) transgene increases energy expenditure. On the contrary, during nocturnal activity period, the presence of either Cra/+ mutation or SOD1(G93A) transgene increases energy expenditure. N = 9 mice per group. C-D- Respiratory quotient of the same mice than in A. The four groups of mice are shown in two graphs for clarity reasons. Mice non transgenic for SOD1(G93A) (SOD1m) are shown in panel C (filled symbols, +/+; empty symbols, Cra/+). Mice transgenic for SOD1(G93A) are shown in panel D (filled symbols, +/+; empty symbols, Cra/+). Note that the presence of a dynein mutation increases respiratory quotient in otherwise wild type mice, and even more potently in SOD1(G93A) mice.
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Related In: Results  -  Collection

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Figure 2: Dynein mutation does not decrease global hypermetabolism but shifts energy metabolism of SOD1(G93A) mice towards carbohydrate use. A- Total (left panel) and resting (right panel) energy expenditure 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. Note that SOD1(G93A) mice are hypermetabolic and that the dynein mutant genotype has no effect on this hypermetabolism. N = 9 mice per group. B- Energy expenditure of the same mice than in A as a function of time. Mice bearing a Cra dynein mutation are denoted by empty symbols, and their corresponding controls by a filled symbol. Mice bearing a SOD1(G93A) (SOD1m) transgene are labeled by a squared symbol and their controls by a circle. Note that in the diurnal period, there are no differences between +/+ and Cra/+ mice but that the presence of a SOD1(G93A) transgene increases energy expenditure. On the contrary, during nocturnal activity period, the presence of either Cra/+ mutation or SOD1(G93A) transgene increases energy expenditure. N = 9 mice per group. C-D- Respiratory quotient of the same mice than in A. The four groups of mice are shown in two graphs for clarity reasons. Mice non transgenic for SOD1(G93A) (SOD1m) are shown in panel C (filled symbols, +/+; empty symbols, Cra/+). Mice transgenic for SOD1(G93A) are shown in panel D (filled symbols, +/+; empty symbols, Cra/+). Note that the presence of a dynein mutation increases respiratory quotient in otherwise wild type mice, and even more potently in SOD1(G93A) mice.
Mentions: We next determined whether the Cramping dynein mutation compensated for energy deficit through decreased SOD1(G93A) linked hypermetabolism. For this, we measured energy expenditure of the four groups of mice. As previously shown [3], SOD1(G93A) animals had a 15-20% increase in resting energy expenditure (Figure 2A), and this hypermetabolism was unchanged by Cramping dynein mutation. Furthermore, SOD1(G93A) associated increased total energy expenditure was also unchanged (Figure 2A) suggesting that the compensation in energy deficit was not provided by, for instance, decreased activity. Thus, the protective potential of Cramping dynein mutation was independent of a direct modulation of global hypermetabolism. Closer examination of indirect calorimetry results revealed however that oxygen consumption of SOD1(G93A) and Cra/SOD1(G93A) but also Cra/+ mice were increased during the nocturnal period as compared with +/+ littermates (Figure 2B). The respiratory quotient of Cra/+ and Cra/SOD1(G93A) mice was higher than that of +/+ and SOD1(G93A) mice at the same period (Figure 2C-D). Since oxidation of carbohydrates leads to a respiratory quotient of 1, while oxidation of lipids leads to a respiratory quotient of 0.7 [17], these results show that the dynein mutation leads to a shift in nutrient use during activity towards preferential carbohydrate oxidation, and thus sparing of lipids and increased fat pad weights.

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