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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 increases liver IGF-1 expression. A- mRNA levels of Insulin-like growth factor (IGF-1) in the liver 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; #, p < 0.05 as indicated. N = 9 mice per group. B- mRNA levels of Insulin-like growth factor (IGF-1) and its muscle specific splice variant mechano-growth factor (MGF) in the gastrocnemius muscle of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns). N = 9 mice per group. C- Serum IGF-1 levels in wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) #, p < 0.05 as indicated. Note that circulating IGF-1 levels are increased in dynein mutant mice and that this increase is abolished in compound SOD1(G93A)/Cra mice. N = 9 mice per group.
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Figure 4: Dynein mutation increases liver IGF-1 expression. A- mRNA levels of Insulin-like growth factor (IGF-1) in the liver 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; #, p < 0.05 as indicated. N = 9 mice per group. B- mRNA levels of Insulin-like growth factor (IGF-1) and its muscle specific splice variant mechano-growth factor (MGF) in the gastrocnemius muscle of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns). N = 9 mice per group. C- Serum IGF-1 levels in wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) #, p < 0.05 as indicated. Note that circulating IGF-1 levels are increased in dynein mutant mice and that this increase is abolished in compound SOD1(G93A)/Cra mice. N = 9 mice per group.

Mentions: We next turned to define potential underlying mechanisms linking energy deficit and motor neuron survival. One candidate mechanism could involve IGF-1. Circulating IGF-1 is a growth factor mainly produced by the liver, but also, in lesser amounts, in other cell types, including muscle, astrocytes and neurons. IGF-1 has been reported to exert neuroprotective effects [22] and to delay motor neuron loss in SOD1(G93A) mice after administration in an early stage of the disease [23,24]. IGF-1 expression is known to be decreased upon energy deficit [25]. In SOD1(G93A) mice, liver IGF-1 expression was decreased of about 30% (Figure 4A), a situation similar to massive energy deficit triggered by 60% caloric restriction [25]. Consistent with reversal of energy deficit, the Cramping dynein mutation completely reverted IGF-1 mRNA downregulation, and even increased it (Figure 4A). Skeletal muscle IGF-1 mRNA levels were unchanged as were mRNA levels of mechano- growth factor, a muscle specific splice variant of IGF-1 [26] (Figure 4B) suggesting that these changes in IGF-1 mRNA levels were restricted to the liver. We next wanted to determine whether hepatic IGF-1 upregulation translated into increased circulating IGF-1. In SOD1(G93A) mice, plasma IGF-1 levels were surprisingly unchanged, suggesting that other mechanisms, including transcription in other cell types or regulated translation of hepatic IGF-1 mRNA occurred [27]. Plasma IGF-1 levels were modestly increased in Cramping dynein mutant mice but not in Cra/SOD1(G93A) mice (Figure 4C). IGF-1 is poorly but significantly transported throughout the blood brain barrier [28-30] in normal conditions and its entry into the CNS is regulated by neuronal activity [31]. Since the blood brain barrier of SOD1(G93A) mice is disrupted [32,33], it is plausible that an increased fraction of IGF-1 is retained in the spinal cord of Cra/SOD1(G93A) mice. Indeed, spinal IGF-1 was increased in Cramping dynein mutant mice and this was further enhanced by the SOD1(G93A) transgene (Figure 5A). IGF-1 mRNA levels were unchanged in the spinal cord (Figure 5B) arguing against the proposal that these increased spinal levels of IGF-1 were due to increased local transcription. Last, mRNA levels of MMP-9 were partially restored by the Cramping dynein mutation (Figure 5C) consistent with the hypothesis of increased IGF-1 transcytosis upon dynein mutation. Thus, the dynein mutation increases availability of IGF-1 to motor neurons in the spinal cord. The increased systemic production of IGF-1 by the liver might be the source of increased spinal IGF-1. Such a mechanism could account for the neuroprotective effects of the dynein mutation towards SOD1(G93A) pathology.


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 increases liver IGF-1 expression. A- mRNA levels of Insulin-like growth factor (IGF-1) in the liver 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; #, p < 0.05 as indicated. N = 9 mice per group. B- mRNA levels of Insulin-like growth factor (IGF-1) and its muscle specific splice variant mechano-growth factor (MGF) in the gastrocnemius muscle of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns). N = 9 mice per group. C- Serum IGF-1 levels in wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) #, p < 0.05 as indicated. Note that circulating IGF-1 levels are increased in dynein mutant mice and that this increase is abolished in compound SOD1(G93A)/Cra mice. N = 9 mice per group.
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Figure 4: Dynein mutation increases liver IGF-1 expression. A- mRNA levels of Insulin-like growth factor (IGF-1) in the liver 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; #, p < 0.05 as indicated. N = 9 mice per group. B- mRNA levels of Insulin-like growth factor (IGF-1) and its muscle specific splice variant mechano-growth factor (MGF) in the gastrocnemius muscle of wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns). N = 9 mice per group. C- Serum IGF-1 levels in wild type (+/+) and dynein mutant mice (Cra/+) bearing SOD1(G93A) transgene (SOD1m, black columns) or not (Wt, empty columns) #, p < 0.05 as indicated. Note that circulating IGF-1 levels are increased in dynein mutant mice and that this increase is abolished in compound SOD1(G93A)/Cra mice. N = 9 mice per group.
Mentions: We next turned to define potential underlying mechanisms linking energy deficit and motor neuron survival. One candidate mechanism could involve IGF-1. Circulating IGF-1 is a growth factor mainly produced by the liver, but also, in lesser amounts, in other cell types, including muscle, astrocytes and neurons. IGF-1 has been reported to exert neuroprotective effects [22] and to delay motor neuron loss in SOD1(G93A) mice after administration in an early stage of the disease [23,24]. IGF-1 expression is known to be decreased upon energy deficit [25]. In SOD1(G93A) mice, liver IGF-1 expression was decreased of about 30% (Figure 4A), a situation similar to massive energy deficit triggered by 60% caloric restriction [25]. Consistent with reversal of energy deficit, the Cramping dynein mutation completely reverted IGF-1 mRNA downregulation, and even increased it (Figure 4A). Skeletal muscle IGF-1 mRNA levels were unchanged as were mRNA levels of mechano- growth factor, a muscle specific splice variant of IGF-1 [26] (Figure 4B) suggesting that these changes in IGF-1 mRNA levels were restricted to the liver. We next wanted to determine whether hepatic IGF-1 upregulation translated into increased circulating IGF-1. In SOD1(G93A) mice, plasma IGF-1 levels were surprisingly unchanged, suggesting that other mechanisms, including transcription in other cell types or regulated translation of hepatic IGF-1 mRNA occurred [27]. Plasma IGF-1 levels were modestly increased in Cramping dynein mutant mice but not in Cra/SOD1(G93A) mice (Figure 4C). IGF-1 is poorly but significantly transported throughout the blood brain barrier [28-30] in normal conditions and its entry into the CNS is regulated by neuronal activity [31]. Since the blood brain barrier of SOD1(G93A) mice is disrupted [32,33], it is plausible that an increased fraction of IGF-1 is retained in the spinal cord of Cra/SOD1(G93A) mice. Indeed, spinal IGF-1 was increased in Cramping dynein mutant mice and this was further enhanced by the SOD1(G93A) transgene (Figure 5A). IGF-1 mRNA levels were unchanged in the spinal cord (Figure 5B) arguing against the proposal that these increased spinal levels of IGF-1 were due to increased local transcription. Last, mRNA levels of MMP-9 were partially restored by the Cramping dynein mutation (Figure 5C) consistent with the hypothesis of increased IGF-1 transcytosis upon dynein mutation. Thus, the dynein mutation increases availability of IGF-1 to motor neurons in the spinal cord. The increased systemic production of IGF-1 by the liver might be the source of increased spinal IGF-1. Such a mechanism could account for the neuroprotective effects of the dynein mutation towards SOD1(G93A) pathology.

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