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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

Phosphofructokinase 1 is inhibited in glycolytic muscle and glucose is rerouted toward glycogen storesEnzymatic activity of phosphofructokinase in whole tibialis anterior muscle cytosolic homogenates is expressed as mean fold change ± SEM from age-matched WT at 65 days of age *P = 0.016 (WT n = 6, SOD1G86Rn = 7) and 105 days of age ***P < 0.0001 (n = 5/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Pyruvate was measured in whole tibialis anterior muscle tissue homogenates. The mean fold change ± SEM compared to age-matched WT are represented with *P = 0.019 at 65 days of age (n = 5/genotype) and *P = 0.041 at 105 days of age (n = 4/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Left: Representative Western blot showing glycogen synthase and phosphorylated glycogen synthase levels. Right: Quantification represents the mean ratio of optical densities of glycogen synthase/P-glycogen synthase ± SEM. At 65 days of age n = 6/genotype, *P = 0.0162, and at 105 days of age n = 5/genotype, *P = 0.0163, two-way ANOVA followed by Fisher's LSD post hoc test.Left: Representative microphotographs of PAS staining from WT and SOD1G86Rtibialis anterior cross-sections at 65 and 105 days of age showing glycogen-negative (light pink) and glycogen-positive (dark pink) fibers. Scale bar: 200 μm. Right: Quantification of glycogen-negative (−) and glycogen-positive (+) fibers at 65 and 105 days of age. For (−) fibers: **P-values versus WT: 0.0026 at 65 days and 0.0074 at 105 days, for (+) fibers: ##P-values versus WT: 0.0025 at 65 days and 0.0073 at 105 days (n = 5/genotype at 65 days and n = 4/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig03: Phosphofructokinase 1 is inhibited in glycolytic muscle and glucose is rerouted toward glycogen storesEnzymatic activity of phosphofructokinase in whole tibialis anterior muscle cytosolic homogenates is expressed as mean fold change ± SEM from age-matched WT at 65 days of age *P = 0.016 (WT n = 6, SOD1G86Rn = 7) and 105 days of age ***P < 0.0001 (n = 5/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Pyruvate was measured in whole tibialis anterior muscle tissue homogenates. The mean fold change ± SEM compared to age-matched WT are represented with *P = 0.019 at 65 days of age (n = 5/genotype) and *P = 0.041 at 105 days of age (n = 4/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Left: Representative Western blot showing glycogen synthase and phosphorylated glycogen synthase levels. Right: Quantification represents the mean ratio of optical densities of glycogen synthase/P-glycogen synthase ± SEM. At 65 days of age n = 6/genotype, *P = 0.0162, and at 105 days of age n = 5/genotype, *P = 0.0163, two-way ANOVA followed by Fisher's LSD post hoc test.Left: Representative microphotographs of PAS staining from WT and SOD1G86Rtibialis anterior cross-sections at 65 and 105 days of age showing glycogen-negative (light pink) and glycogen-positive (dark pink) fibers. Scale bar: 200 μm. Right: Quantification of glycogen-negative (−) and glycogen-positive (+) fibers at 65 and 105 days of age. For (−) fibers: **P-values versus WT: 0.0026 at 65 days and 0.0074 at 105 days, for (+) fibers: ##P-values versus WT: 0.0025 at 65 days and 0.0073 at 105 days (n = 5/genotype at 65 days and n = 4/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).

Mentions: To determine whether altered glucose handling occurred at the level of skeletal muscle, we assessed the activity of phosphofructokinase 1 (PFK1), the rate-limiting enzyme of glycolysis, in TA cytosolic homogenates (Fig3A). When compared to WT littermates, SOD1G86R mice had a significant 23% reduction in PFK1 enzymatic activity at 65 days of age. By the end stage of disease (105 days of age), PFK1 activity was reduced by 88.8% in SOD1G86R mice when compared to WT littermates. This was accompanied by a 5-fold down-regulation in the expression of Pfk1 mRNA in SOD1G86R mice (Supplementary Fig S1C). Interestingly, a 4-fold down-regulation in the expression of Pfk1 mRNA was also observed in SOD1G93A mice, another ALS mouse model, at the end stage of disease (Supplementary Fig S2B).


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)

Phosphofructokinase 1 is inhibited in glycolytic muscle and glucose is rerouted toward glycogen storesEnzymatic activity of phosphofructokinase in whole tibialis anterior muscle cytosolic homogenates is expressed as mean fold change ± SEM from age-matched WT at 65 days of age *P = 0.016 (WT n = 6, SOD1G86Rn = 7) and 105 days of age ***P < 0.0001 (n = 5/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Pyruvate was measured in whole tibialis anterior muscle tissue homogenates. The mean fold change ± SEM compared to age-matched WT are represented with *P = 0.019 at 65 days of age (n = 5/genotype) and *P = 0.041 at 105 days of age (n = 4/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Left: Representative Western blot showing glycogen synthase and phosphorylated glycogen synthase levels. Right: Quantification represents the mean ratio of optical densities of glycogen synthase/P-glycogen synthase ± SEM. At 65 days of age n = 6/genotype, *P = 0.0162, and at 105 days of age n = 5/genotype, *P = 0.0163, two-way ANOVA followed by Fisher's LSD post hoc test.Left: Representative microphotographs of PAS staining from WT and SOD1G86Rtibialis anterior cross-sections at 65 and 105 days of age showing glycogen-negative (light pink) and glycogen-positive (dark pink) fibers. Scale bar: 200 μm. Right: Quantification of glycogen-negative (−) and glycogen-positive (+) fibers at 65 and 105 days of age. For (−) fibers: **P-values versus WT: 0.0026 at 65 days and 0.0074 at 105 days, for (+) fibers: ##P-values versus WT: 0.0025 at 65 days and 0.0073 at 105 days (n = 5/genotype at 65 days and n = 4/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig03: Phosphofructokinase 1 is inhibited in glycolytic muscle and glucose is rerouted toward glycogen storesEnzymatic activity of phosphofructokinase in whole tibialis anterior muscle cytosolic homogenates is expressed as mean fold change ± SEM from age-matched WT at 65 days of age *P = 0.016 (WT n = 6, SOD1G86Rn = 7) and 105 days of age ***P < 0.0001 (n = 5/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Pyruvate was measured in whole tibialis anterior muscle tissue homogenates. The mean fold change ± SEM compared to age-matched WT are represented with *P = 0.019 at 65 days of age (n = 5/genotype) and *P = 0.041 at 105 days of age (n = 4/genotype), two-way ANOVA followed by Fisher's LSD post hoc test. Data shown are representative of two independent experiments having similar results.Left: Representative Western blot showing glycogen synthase and phosphorylated glycogen synthase levels. Right: Quantification represents the mean ratio of optical densities of glycogen synthase/P-glycogen synthase ± SEM. At 65 days of age n = 6/genotype, *P = 0.0162, and at 105 days of age n = 5/genotype, *P = 0.0163, two-way ANOVA followed by Fisher's LSD post hoc test.Left: Representative microphotographs of PAS staining from WT and SOD1G86Rtibialis anterior cross-sections at 65 and 105 days of age showing glycogen-negative (light pink) and glycogen-positive (dark pink) fibers. Scale bar: 200 μm. Right: Quantification of glycogen-negative (−) and glycogen-positive (+) fibers at 65 and 105 days of age. For (−) fibers: **P-values versus WT: 0.0026 at 65 days and 0.0074 at 105 days, for (+) fibers: ##P-values versus WT: 0.0025 at 65 days and 0.0073 at 105 days (n = 5/genotype at 65 days and n = 4/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
Mentions: To determine whether altered glucose handling occurred at the level of skeletal muscle, we assessed the activity of phosphofructokinase 1 (PFK1), the rate-limiting enzyme of glycolysis, in TA cytosolic homogenates (Fig3A). When compared to WT littermates, SOD1G86R mice had a significant 23% reduction in PFK1 enzymatic activity at 65 days of age. By the end stage of disease (105 days of age), PFK1 activity was reduced by 88.8% in SOD1G86R mice when compared to WT littermates. This was accompanied by a 5-fold down-regulation in the expression of Pfk1 mRNA in SOD1G86R mice (Supplementary Fig S1C). Interestingly, a 4-fold down-regulation in the expression of Pfk1 mRNA was also observed in SOD1G93A mice, another ALS mouse model, at the end stage of disease (Supplementary Fig S2B).

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