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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 beneficial effects on metabolism and mitochondrial function of SOD1G86R miceA–I Relative mRNA levels of (A) Pdk4, (B) Pparβ/δ, (C) Foxo1, (D) Pfk1, (E) Acsf2, (F) citrate synthase, (G) PGC-1α, (H) Mfn2, and (I) Gpx1 were evaluated 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-values versus WT: Pdk4 ***P = 0.002 and ##P = 0.0039, Pparβ/δ#P = 0.0178, Foxo1 **P = 0.0033 and ##P = 0.0038, Pfk1 ***P = 0.0002 and ##P = 0.0080, Acsf2 *P = 0.0437, citrate synthase###P = 0.0004, Pgc-1α **P = 0.0084 and ###P = 0.0009, Mfn2 *P = 0.0272, $P = 0.0145 and ###P = 0.0002 and Gpx1 ***P < 0.0001 and ###P < 0.0001 (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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fig07: DCA treatment had beneficial effects on metabolism and mitochondrial function of SOD1G86R miceA–I Relative mRNA levels of (A) Pdk4, (B) Pparβ/δ, (C) Foxo1, (D) Pfk1, (E) Acsf2, (F) citrate synthase, (G) PGC-1α, (H) Mfn2, and (I) Gpx1 were evaluated 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-values versus WT: Pdk4 ***P = 0.002 and ##P = 0.0039, Pparβ/δ#P = 0.0178, Foxo1 **P = 0.0033 and ##P = 0.0038, Pfk1 ***P = 0.0002 and ##P = 0.0080, Acsf2 *P = 0.0437, citrate synthase###P = 0.0004, Pgc-1α **P = 0.0084 and ###P = 0.0009, Mfn2 *P = 0.0272, $P = 0.0145 and ###P = 0.0002 and Gpx1 ***P < 0.0001 and ###P < 0.0001 (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: Daily administration of DCA was able to reverse the changes in Pdk4, Pparβ/δ, and Foxo1 mRNA expression in SOD1G86R mice (DCA) when compared to non-DCA-treated SOD1G86R mice (CT, Fig7A–C). At the cessation of treatment, Pfk1, Acsf2, and citrate synthase mRNA levels in DCA-treated SOD1G86R mice were comparable to DCA-treated WT mice (Fig7D–F), indicating successful restoration of glycolysis and activation of the Krebs cycle. Importantly, CT SOD1G86R mice presented with significantly reduced Pfk1 and citrate synthase expression when compared to DCA-treated SOD1G86R mice and/or CT WT mice. DCA treatment was also able to preserve the expression of Pgc-1α and its target gene Mfn2 in DCA-treated SOD1G86R mice at levels comparable to that seen in CT WT and DCA-treated WT mice (Fig7G and H). The increase in the expression of genes involved in mitochondrial biogenesis was accompanied by a decrease in the expression of the Gpx1 (Fig7I). Notably, and in support of our results above, 95-day-old CT SOD1G86R mice presented with a significant decrease in the expression of Pgc-1α and Mfn2 mRNA and an increase in the expression of Gpx1 mRNA (Fig7G–I). Collectively, these data suggest that DCA is able to restore glycolytic function while decreasing oxidative stress in glycolytic muscle of 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 beneficial effects on metabolism and mitochondrial function of SOD1G86R miceA–I Relative mRNA levels of (A) Pdk4, (B) Pparβ/δ, (C) Foxo1, (D) Pfk1, (E) Acsf2, (F) citrate synthase, (G) PGC-1α, (H) Mfn2, and (I) Gpx1 were evaluated 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-values versus WT: Pdk4 ***P = 0.002 and ##P = 0.0039, Pparβ/δ#P = 0.0178, Foxo1 **P = 0.0033 and ##P = 0.0038, Pfk1 ***P = 0.0002 and ##P = 0.0080, Acsf2 *P = 0.0437, citrate synthase###P = 0.0004, Pgc-1α **P = 0.0084 and ###P = 0.0009, Mfn2 *P = 0.0272, $P = 0.0145 and ###P = 0.0002 and Gpx1 ***P < 0.0001 and ###P < 0.0001 (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).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig07: DCA treatment had beneficial effects on metabolism and mitochondrial function of SOD1G86R miceA–I Relative mRNA levels of (A) Pdk4, (B) Pparβ/δ, (C) Foxo1, (D) Pfk1, (E) Acsf2, (F) citrate synthase, (G) PGC-1α, (H) Mfn2, and (I) Gpx1 were evaluated 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-values versus WT: Pdk4 ***P = 0.002 and ##P = 0.0039, Pparβ/δ#P = 0.0178, Foxo1 **P = 0.0033 and ##P = 0.0038, Pfk1 ***P = 0.0002 and ##P = 0.0080, Acsf2 *P = 0.0437, citrate synthase###P = 0.0004, Pgc-1α **P = 0.0084 and ###P = 0.0009, Mfn2 *P = 0.0272, $P = 0.0145 and ###P = 0.0002 and Gpx1 ***P < 0.0001 and ###P < 0.0001 (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: Daily administration of DCA was able to reverse the changes in Pdk4, Pparβ/δ, and Foxo1 mRNA expression in SOD1G86R mice (DCA) when compared to non-DCA-treated SOD1G86R mice (CT, Fig7A–C). At the cessation of treatment, Pfk1, Acsf2, and citrate synthase mRNA levels in DCA-treated SOD1G86R mice were comparable to DCA-treated WT mice (Fig7D–F), indicating successful restoration of glycolysis and activation of the Krebs cycle. Importantly, CT SOD1G86R mice presented with significantly reduced Pfk1 and citrate synthase expression when compared to DCA-treated SOD1G86R mice and/or CT WT mice. DCA treatment was also able to preserve the expression of Pgc-1α and its target gene Mfn2 in DCA-treated SOD1G86R mice at levels comparable to that seen in CT WT and DCA-treated WT mice (Fig7G and H). The increase in the expression of genes involved in mitochondrial biogenesis was accompanied by a decrease in the expression of the Gpx1 (Fig7I). Notably, and in support of our results above, 95-day-old CT SOD1G86R mice presented with a significant decrease in the expression of Pgc-1α and Mfn2 mRNA and an increase in the expression of Gpx1 mRNA (Fig7G–I). Collectively, these data suggest that DCA is able to restore glycolytic function while decreasing oxidative stress in glycolytic muscle of 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