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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

Transcription factors, PGC-1α, and citrate synthase are differentially regulated in SOD1G86R miceA–D Relative mRNA levels of (A) Pparß/δ, (B) Foxo1, (C) citrate synthase, and (D) Pgc-1α were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: Pparβ/δ **P = 0.0016 at 65 days; Foxo1 ***P = 0.0001 at 105 days, citrate synthase ***P < 0.0001 at 105 days, Pgc-1α *P = 0.0104 at 105 days (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).E Representative Western blot of PGC-1α and respective actin that was used for normalization. PGC-1α protein levels in tibialis anterior muscle tissue are represented as mean fold change ± SEM from age-matched WT. **P-values versus WT: 0.02 (n = 6/genotype at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).F Relative mRNA levels of ERRα, Mfn2, and Nrf1 were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: ERRα ***P < 0.0001, Mfn2 **P = 0.002 and Nrf1 **P = 0.009 (n = 6–7 and 7–8 for WT and SOD1G86R, respectively, at 65 days; n = 5 and 6 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig05: Transcription factors, PGC-1α, and citrate synthase are differentially regulated in SOD1G86R miceA–D Relative mRNA levels of (A) Pparß/δ, (B) Foxo1, (C) citrate synthase, and (D) Pgc-1α were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: Pparβ/δ **P = 0.0016 at 65 days; Foxo1 ***P = 0.0001 at 105 days, citrate synthase ***P < 0.0001 at 105 days, Pgc-1α *P = 0.0104 at 105 days (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).E Representative Western blot of PGC-1α and respective actin that was used for normalization. PGC-1α protein levels in tibialis anterior muscle tissue are represented as mean fold change ± SEM from age-matched WT. **P-values versus WT: 0.02 (n = 6/genotype at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).F Relative mRNA levels of ERRα, Mfn2, and Nrf1 were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: ERRα ***P < 0.0001, Mfn2 **P = 0.002 and Nrf1 **P = 0.009 (n = 6–7 and 7–8 for WT and SOD1G86R, respectively, at 65 days; n = 5 and 6 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).

Mentions: Increased expression of genes encoding an enzyme that hydrolyses triglycerides to facilitate the uptake of free fatty acids (LPL) (Mead et al, 2002), a membrane translocase that promotes FA entry into the cell (CD36), an enzyme that catalyses the conversion of FA to AcylCoA (ACSF2), and the rate-limiting enzyme for β-oxidation responsible for the FA transfer into the mitochondria (CPT-1B) (McGarry et al, 1983) in asymptomatic SOD1G86R mice suggests that fatty acids intake is increased into glycolytic muscle tissue when ALS occurs. Taken together with the increased expression of Pdk4, our data indicate that higher levels of β-oxidation exist in glycolytic muscle prior to denervation. Given that adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH) are two energetic substrates produced by β-oxidation and oxidative phosphorylation in the mitochondria that are known to stimulate PDK activity (for review, see Harris et al, 2002), we measured the variation in these molecules in the TA of SOD1G86R mice and WT littermates at 65 and 105 days of age. We evidenced a significant increase in ATP and NADH levels (1.37- and 1.49-fold change, respectively) in 65-day-old SOD1G86R mice compared to WT while NAD+ levels were comparable (Fig4C). Interestingly, ATP and NADH levels were similar between SOD1G86R mice and WT littermates at 105 days of age while NAD+ levels were increased 2.6-fold. Finally, mRNA levels of Pparβ/δ and Foxo1 were increased in 65-day-old SOD1G86R mice (Fig5A and B). Further, mRNA levels of citrate synthase, the first enzyme of the Krebs cycle, were comparable to WT at 65 days of age but significantly reduced at end stage (Fig5C). These data, together with the inhibition of glycolysis described in the previous section, clearly demonstrate that an early change in fuel preference from glucose toward lipids in glycolytic muscle fibers occurs before denervation 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)

Transcription factors, PGC-1α, and citrate synthase are differentially regulated in SOD1G86R miceA–D Relative mRNA levels of (A) Pparß/δ, (B) Foxo1, (C) citrate synthase, and (D) Pgc-1α were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: Pparβ/δ **P = 0.0016 at 65 days; Foxo1 ***P = 0.0001 at 105 days, citrate synthase ***P < 0.0001 at 105 days, Pgc-1α *P = 0.0104 at 105 days (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).E Representative Western blot of PGC-1α and respective actin that was used for normalization. PGC-1α protein levels in tibialis anterior muscle tissue are represented as mean fold change ± SEM from age-matched WT. **P-values versus WT: 0.02 (n = 6/genotype at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).F Relative mRNA levels of ERRα, Mfn2, and Nrf1 were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: ERRα ***P < 0.0001, Mfn2 **P = 0.002 and Nrf1 **P = 0.009 (n = 6–7 and 7–8 for WT and SOD1G86R, respectively, at 65 days; n = 5 and 6 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig05: Transcription factors, PGC-1α, and citrate synthase are differentially regulated in SOD1G86R miceA–D Relative mRNA levels of (A) Pparß/δ, (B) Foxo1, (C) citrate synthase, and (D) Pgc-1α were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: Pparβ/δ **P = 0.0016 at 65 days; Foxo1 ***P = 0.0001 at 105 days, citrate synthase ***P < 0.0001 at 105 days, Pgc-1α *P = 0.0104 at 105 days (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).E Representative Western blot of PGC-1α and respective actin that was used for normalization. PGC-1α protein levels in tibialis anterior muscle tissue are represented as mean fold change ± SEM from age-matched WT. **P-values versus WT: 0.02 (n = 6/genotype at 65 days; n = 5/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).F Relative mRNA levels of ERRα, Mfn2, and Nrf1 were evaluated by qPCR at the indicated ages in tibialis anterior of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. P-values versus WT: ERRα ***P < 0.0001, Mfn2 **P = 0.002 and Nrf1 **P = 0.009 (n = 6–7 and 7–8 for WT and SOD1G86R, respectively, at 65 days; n = 5 and 6 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
Mentions: Increased expression of genes encoding an enzyme that hydrolyses triglycerides to facilitate the uptake of free fatty acids (LPL) (Mead et al, 2002), a membrane translocase that promotes FA entry into the cell (CD36), an enzyme that catalyses the conversion of FA to AcylCoA (ACSF2), and the rate-limiting enzyme for β-oxidation responsible for the FA transfer into the mitochondria (CPT-1B) (McGarry et al, 1983) in asymptomatic SOD1G86R mice suggests that fatty acids intake is increased into glycolytic muscle tissue when ALS occurs. Taken together with the increased expression of Pdk4, our data indicate that higher levels of β-oxidation exist in glycolytic muscle prior to denervation. Given that adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH) are two energetic substrates produced by β-oxidation and oxidative phosphorylation in the mitochondria that are known to stimulate PDK activity (for review, see Harris et al, 2002), we measured the variation in these molecules in the TA of SOD1G86R mice and WT littermates at 65 and 105 days of age. We evidenced a significant increase in ATP and NADH levels (1.37- and 1.49-fold change, respectively) in 65-day-old SOD1G86R mice compared to WT while NAD+ levels were comparable (Fig4C). Interestingly, ATP and NADH levels were similar between SOD1G86R mice and WT littermates at 105 days of age while NAD+ levels were increased 2.6-fold. Finally, mRNA levels of Pparβ/δ and Foxo1 were increased in 65-day-old SOD1G86R mice (Fig5A and B). Further, mRNA levels of citrate synthase, the first enzyme of the Krebs cycle, were comparable to WT at 65 days of age but significantly reduced at end stage (Fig5C). These data, together with the inhibition of glycolysis described in the previous section, clearly demonstrate that an early change in fuel preference from glucose toward lipids in glycolytic muscle fibers occurs before denervation 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