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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 reverts the systemic and molecular alterations associated with energy deficit in SOD1(G93A) mice. A- mRNA levels of lipoprotein lipase (LPL) in the epididimary white fat pad 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. Note that the SOD1(G93A)-associated decreased expression of LPL in the EPI is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. B- mRNA levels of fatty acid synthase (FAS), carnithine palmitoyl transferase 1A (liver form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor alpha (PPARα), peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α), phosphoenolpyruvate carboxykinase (PEPCK) and peroxisome-proliferator activated receptor gamma (PPARγ) in the liver of the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. Note that the SOD1(G93A)-associated decreased expression of FAS in the liver is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. C- Circulating triglycerides levels in the same mice than in A either in fed (right) or fasted conditions (left). Note that the SOD1(G93A) transgene leads to decreased fed triglycerides levels and that this is partially reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. D- Circulating non-esterified fatty acids (NEFAs) levels in the same mice than in A in fasted conditions. Note that the SOD1(G93A) transgene leads to decreased fasted NEFAs levels and that this is fully reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. E- mRNA levels of carnithine palmitoyl transferase 1B (muscle form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α) in the gastrocnemius muscle of the same mice than in A. *P < 0.05 versus Wt. N = 9 mice per group.
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Figure 3: Dynein mutation reverts the systemic and molecular alterations associated with energy deficit in SOD1(G93A) mice. A- mRNA levels of lipoprotein lipase (LPL) in the epididimary white fat pad 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. Note that the SOD1(G93A)-associated decreased expression of LPL in the EPI is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. B- mRNA levels of fatty acid synthase (FAS), carnithine palmitoyl transferase 1A (liver form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor alpha (PPARα), peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α), phosphoenolpyruvate carboxykinase (PEPCK) and peroxisome-proliferator activated receptor gamma (PPARγ) in the liver of the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. Note that the SOD1(G93A)-associated decreased expression of FAS in the liver is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. C- Circulating triglycerides levels in the same mice than in A either in fed (right) or fasted conditions (left). Note that the SOD1(G93A) transgene leads to decreased fed triglycerides levels and that this is partially reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. D- Circulating non-esterified fatty acids (NEFAs) levels in the same mice than in A in fasted conditions. Note that the SOD1(G93A) transgene leads to decreased fasted NEFAs levels and that this is fully reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. E- mRNA levels of carnithine palmitoyl transferase 1B (muscle form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α) in the gastrocnemius muscle of the same mice than in A. *P < 0.05 versus Wt. N = 9 mice per group.

Mentions: The decreased lipid oxidation in mice bearing the Cramping mutation might be due to their blunted ability to mobilize adipose stores as previously documented [15]. We thus sought to determine whether the increased fat pad weights also reflected a better metabolic status of the mice. Fatty acid synthase (FAS) expression in the liver and Lipoprotein lipase (LPL) expression in white adipose tissue are well known for their regulated expression as a function of nutritional and hormonal cues [18-21]. Most notably, these two genes are profoundly downregulated by energy deficit, including starvation as well as in SOD1(G93A) mice. Here, the Cramping dynein mutation was able to revert these down-regulations in Cra/SOD1(G93A) mice (Figure 3A-B). This increased expression of FAS was associated with unchanged expression of beta-oxidation enzymes such as CPT1A and MCAD or gluconeogenesis enzymes such as PEPCK in the liver (Figure 3B). However, expression levels of PPARα and PGC1α, two critical players in the transcriptional control of liver beta-oxidation were decreased by expression of SOD1(G93A) and expression of PPARγ was increased. The Cramping dynein mutation reverted PPARα and PGC1α downregulations and potentiated PPARγ upregulation in Cra/SOD1(G93A) mice (Figure 3B). A hallmark of energy homeostasis defect in SOD1(G93A) mice is the occurrence of decreased circulating triglycerides after feeding [2]. Consistent with these studies, fed, but not fasted; triglycerides were decreased in SOD1(G93A) mice. The Cramping dynein mutation partially compensated for this defect (Figure 3C). Upon fasting, non-esterified fatty acids levels were decreased in SOD1(G93A) mice, as a likely result of increased muscle uptake [2,3], and this was fully reverted by the Cramping mutation (Figure 3D). The effect of dynein mutation on metabolic gene expression was not observed in skeletal muscle, in which gene expression of MCAD, CPT1B and PGC1α were unaffected by either SOD1(G93A) or Cramping dynein mutation (Figure 3E). Thus, dynein mutation not only compensates for energy deficit, but also reverts systemic and molecular changes associated with SOD1(G93A) energy deficit.


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 reverts the systemic and molecular alterations associated with energy deficit in SOD1(G93A) mice. A- mRNA levels of lipoprotein lipase (LPL) in the epididimary white fat pad 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. Note that the SOD1(G93A)-associated decreased expression of LPL in the EPI is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. B- mRNA levels of fatty acid synthase (FAS), carnithine palmitoyl transferase 1A (liver form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor alpha (PPARα), peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α), phosphoenolpyruvate carboxykinase (PEPCK) and peroxisome-proliferator activated receptor gamma (PPARγ) in the liver of the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. Note that the SOD1(G93A)-associated decreased expression of FAS in the liver is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. C- Circulating triglycerides levels in the same mice than in A either in fed (right) or fasted conditions (left). Note that the SOD1(G93A) transgene leads to decreased fed triglycerides levels and that this is partially reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. D- Circulating non-esterified fatty acids (NEFAs) levels in the same mice than in A in fasted conditions. Note that the SOD1(G93A) transgene leads to decreased fasted NEFAs levels and that this is fully reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. E- mRNA levels of carnithine palmitoyl transferase 1B (muscle form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α) in the gastrocnemius muscle of the same mice than in A. *P < 0.05 versus Wt. N = 9 mice per group.
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Figure 3: Dynein mutation reverts the systemic and molecular alterations associated with energy deficit in SOD1(G93A) mice. A- mRNA levels of lipoprotein lipase (LPL) in the epididimary white fat pad 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. Note that the SOD1(G93A)-associated decreased expression of LPL in the EPI is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. B- mRNA levels of fatty acid synthase (FAS), carnithine palmitoyl transferase 1A (liver form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor alpha (PPARα), peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α), phosphoenolpyruvate carboxykinase (PEPCK) and peroxisome-proliferator activated receptor gamma (PPARγ) in the liver of the same mice than in A. *P < 0.05 versus Wt; #, p < 0.05 as indicated. Note that the SOD1(G93A)-associated decreased expression of FAS in the liver is rescued by the dynein mutation in compound SOD1(G93A)/Cra mice. N = 9 mice per group. C- Circulating triglycerides levels in the same mice than in A either in fed (right) or fasted conditions (left). Note that the SOD1(G93A) transgene leads to decreased fed triglycerides levels and that this is partially reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. D- Circulating non-esterified fatty acids (NEFAs) levels in the same mice than in A in fasted conditions. Note that the SOD1(G93A) transgene leads to decreased fasted NEFAs levels and that this is fully reverted in compound SOD1(G93A)/Cra mice. N = 9 mice per group. E- mRNA levels of carnithine palmitoyl transferase 1B (muscle form, CPT1A), Medium chain acyl CoA dehydrogenase (MCAD), peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor gamma co-activator 1 alpha (PGC1α) in the gastrocnemius muscle of the same mice than in A. *P < 0.05 versus Wt. N = 9 mice per group.
Mentions: The decreased lipid oxidation in mice bearing the Cramping mutation might be due to their blunted ability to mobilize adipose stores as previously documented [15]. We thus sought to determine whether the increased fat pad weights also reflected a better metabolic status of the mice. Fatty acid synthase (FAS) expression in the liver and Lipoprotein lipase (LPL) expression in white adipose tissue are well known for their regulated expression as a function of nutritional and hormonal cues [18-21]. Most notably, these two genes are profoundly downregulated by energy deficit, including starvation as well as in SOD1(G93A) mice. Here, the Cramping dynein mutation was able to revert these down-regulations in Cra/SOD1(G93A) mice (Figure 3A-B). This increased expression of FAS was associated with unchanged expression of beta-oxidation enzymes such as CPT1A and MCAD or gluconeogenesis enzymes such as PEPCK in the liver (Figure 3B). However, expression levels of PPARα and PGC1α, two critical players in the transcriptional control of liver beta-oxidation were decreased by expression of SOD1(G93A) and expression of PPARγ was increased. The Cramping dynein mutation reverted PPARα and PGC1α downregulations and potentiated PPARγ upregulation in Cra/SOD1(G93A) mice (Figure 3B). A hallmark of energy homeostasis defect in SOD1(G93A) mice is the occurrence of decreased circulating triglycerides after feeding [2]. Consistent with these studies, fed, but not fasted; triglycerides were decreased in SOD1(G93A) mice. The Cramping dynein mutation partially compensated for this defect (Figure 3C). Upon fasting, non-esterified fatty acids levels were decreased in SOD1(G93A) mice, as a likely result of increased muscle uptake [2,3], and this was fully reverted by the Cramping mutation (Figure 3D). The effect of dynein mutation on metabolic gene expression was not observed in skeletal muscle, in which gene expression of MCAD, CPT1B and PGC1α were unaffected by either SOD1(G93A) or Cramping dynein mutation (Figure 3E). Thus, dynein mutation not only compensates for energy deficit, but also reverts systemic and molecular changes associated with SOD1(G93A) energy deficit.

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