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A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis.

Palamiuc L, Schlagowski A, Ngo ST, Vernay A, Dirrig-Grosch S, Henriques A, Boutillier AL, Zoll J, Echaniz-Laguna A, Loeffler JP, René F - EMBO Mol Med (2015)

Bottom Line: This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression.Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation.In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France.

No MeSH data available.


Related in: MedlinePlus

DCA treatment had protective effects on muscle strength and prevented the expression denervation markersGrip strength is represented as mean of percent from T0 for each experimental group ± SEM. ##P = 0.0045 and ***P = 0.0003 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of muscular atrophy markers Murf1 and Atg-1 were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.0079 and ***P = 0.0018 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of denervation markers AChRα, AChRγ, and MuSK were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.015 for AChRα, #P = 0.028 and **P = 0.074 for AChRγ, #P = 0.042 and **P = 0.0029 for MuSK (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig08: DCA treatment had protective effects on muscle strength and prevented the expression denervation markersGrip strength is represented as mean of percent from T0 for each experimental group ± SEM. ##P = 0.0045 and ***P = 0.0003 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of muscular atrophy markers Murf1 and Atg-1 were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.0079 and ***P = 0.0018 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of denervation markers AChRα, AChRγ, and MuSK were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.015 for AChRα, #P = 0.028 and **P = 0.074 for AChRγ, #P = 0.042 and **P = 0.0029 for MuSK (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).

Mentions: At a functional level, DCA was able to almost completely preserve muscle strength. While CT SOD1G86R mice lost 30% of their grip strength, DCA-treated SOD1G86R mice only lost 8% of their grip strength when compared to initial grip force at the initiation of treatment (Fig8A). This increased grip strength was associated with an increase in both oxidative and glycolytic muscle fiber size in TA (Supplementary Fig S7D and E). Analysis of mRNA expression of muscle atrophy markers showed a more modest improvement (Fig8B). Murf-1 mRNA expression was reduced from a 1.6-fold increase in the non-treated CT SOD1G86R mice to 1.3-fold increase in DCA-treated SOD1G86R mice. Similarly, Atg-1 mRNA expression was decreased from a 1.7-fold increase in CT SOD1G86R mice to a 1.4-fold increase in DCA-treated SOD1G86R mice. DCA treatment also prevented the increase in the expression of the denervation markers (Fig8C). The increase in expression of AChRα mRNA in DCA-treated SOD1G86R mice was only 3.2-fold as compared to an 8.8-fold increase in CT SOD1G86R mice. AChRγ mRNA was increased by 3.9-fold in DCA-treated SOD1G86R mice as compared to a 15.87-fold increase measured in CT SOD1G86R mice. Lastly, MuSK gene expression was also lower following treatment with DCA, decreasing from a 2-fold increase in CT SOD1G86R mice to a 1.3-fold increase in DCA-treated SOD1G86R mice. WT mice treated with DCA did not present with any modifications of these atrophy or denervation markers. Altogether, these results demonstrate that by facilitating the equilibrium between glucose and lipid oxidation through the administration of DCA, we are able to promote weight gain, restore mitochondrial gene expression, improve muscle strength, and decrease the expression of denervation markers in SOD1G86R mice.


A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis.

Palamiuc L, Schlagowski A, Ngo ST, Vernay A, Dirrig-Grosch S, Henriques A, Boutillier AL, Zoll J, Echaniz-Laguna A, Loeffler JP, René F - EMBO Mol Med (2015)

DCA treatment had protective effects on muscle strength and prevented the expression denervation markersGrip strength is represented as mean of percent from T0 for each experimental group ± SEM. ##P = 0.0045 and ***P = 0.0003 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of muscular atrophy markers Murf1 and Atg-1 were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.0079 and ***P = 0.0018 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of denervation markers AChRα, AChRγ, and MuSK were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.015 for AChRα, #P = 0.028 and **P = 0.074 for AChRγ, #P = 0.042 and **P = 0.0029 for MuSK (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig08: DCA treatment had protective effects on muscle strength and prevented the expression denervation markersGrip strength is represented as mean of percent from T0 for each experimental group ± SEM. ##P = 0.0045 and ***P = 0.0003 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of muscular atrophy markers Murf1 and Atg-1 were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.0079 and ***P = 0.0018 (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of denervation markers AChRα, AChRγ, and MuSK were measured by qPCR in tibialis anterior of control (CT) or DCA-treated (DCA) WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from CT WT group. **P = 0.015 for AChRα, #P = 0.028 and **P = 0.074 for AChRγ, #P = 0.042 and **P = 0.0029 for MuSK (n = 9/genotype in CT groups, n = 9 and 8 for WT and SOD1G86R, respectively, in DCA group, two-way ANOVA followed by Fisher's LSD post hoc test).
Mentions: At a functional level, DCA was able to almost completely preserve muscle strength. While CT SOD1G86R mice lost 30% of their grip strength, DCA-treated SOD1G86R mice only lost 8% of their grip strength when compared to initial grip force at the initiation of treatment (Fig8A). This increased grip strength was associated with an increase in both oxidative and glycolytic muscle fiber size in TA (Supplementary Fig S7D and E). Analysis of mRNA expression of muscle atrophy markers showed a more modest improvement (Fig8B). Murf-1 mRNA expression was reduced from a 1.6-fold increase in the non-treated CT SOD1G86R mice to 1.3-fold increase in DCA-treated SOD1G86R mice. Similarly, Atg-1 mRNA expression was decreased from a 1.7-fold increase in CT SOD1G86R mice to a 1.4-fold increase in DCA-treated SOD1G86R mice. DCA treatment also prevented the increase in the expression of the denervation markers (Fig8C). The increase in expression of AChRα mRNA in DCA-treated SOD1G86R mice was only 3.2-fold as compared to an 8.8-fold increase in CT SOD1G86R mice. AChRγ mRNA was increased by 3.9-fold in DCA-treated SOD1G86R mice as compared to a 15.87-fold increase measured in CT SOD1G86R mice. Lastly, MuSK gene expression was also lower following treatment with DCA, decreasing from a 2-fold increase in CT SOD1G86R mice to a 1.3-fold increase in DCA-treated SOD1G86R mice. WT mice treated with DCA did not present with any modifications of these atrophy or denervation markers. Altogether, these results demonstrate that by facilitating the equilibrium between glucose and lipid oxidation through the administration of DCA, we are able to promote weight gain, restore mitochondrial gene expression, improve muscle strength, and decrease the expression of denervation markers in SOD1G86R mice.

Bottom Line: This mechanism represents a chronic pathologic alteration in muscle metabolism that is exacerbated with disease progression.Further, inhibition of pyruvate dehydrogenase kinase 4 activity with dichloroacetate delayed symptom onset while improving mitochondrial dysfunction and ameliorating muscle denervation.In this study, we provide the first molecular basis for the particular sensitivity of glycolytic muscles to ALS pathology.

View Article: PubMed Central - PubMed

Affiliation: INSERM, U1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Strasbourg, France Université de Strasbourg UMRS1118, Strasbourg, France.

No MeSH data available.


Related in: MedlinePlus