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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

Altered mitochondrial function in glycolytic muscle of SOD1G86R miceMitochondrial DNA (mtDNA) was quantified using qPCR. Relative mtDNA levels are expressed as the ratio between mitochondrial-encoded gene Cox1 and the nuclear-encoded gene cyclophilin A. Graphs represent mean fold change ± SEM from age-matched WT for tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. ***P < 0.0001 (n = 5 and 4 for WT and SOD1G86R, respectively, at 65 days; n = 6/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of Gpx1 were measured by qPCR at the indicated ages in tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. ***P < 0.0001 (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 9 and 8 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
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fig06: Altered mitochondrial function in glycolytic muscle of SOD1G86R miceMitochondrial DNA (mtDNA) was quantified using qPCR. Relative mtDNA levels are expressed as the ratio between mitochondrial-encoded gene Cox1 and the nuclear-encoded gene cyclophilin A. Graphs represent mean fold change ± SEM from age-matched WT for tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. ***P < 0.0001 (n = 5 and 4 for WT and SOD1G86R, respectively, at 65 days; n = 6/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of Gpx1 were measured by qPCR at the indicated ages in tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. ***P < 0.0001 (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 9 and 8 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).

Mentions: The processes that promote the mobilization and use of fatty acids for ATP synthesis during moderate exercise are subjected to multiple regulatory steps. Typically, increased oxidative capacity and lipid use in muscle is accompanied by a switch in muscle fiber subtype, a phenomenon that is facilitated by peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis and function (Wu et al, 1999; Lin et al, 2002). We thus analyzed the expression of PGC-1α in the TA of SOD1G86R mice. At 65 days of age, Pgc-1α mRNA and protein levels were similar between SOD1G86R and WT mice (Fig5D and E), whereas they were significantly decreased at 105 days of age in SOD1G86R mice. Importantly, at the end stage of the disease the decrease in PGC-1α protein levels correlated with a decrease in the mRNA expression of the main target genes of PGC-1α pathway, estrogen-related receptor α (ERRα), mitofusin 2 (Mfn2), and nuclear respiratory factor 1 (Nrf1) (Puigserver, 2005; Villena & Kralli, 2008) (Fig5E). ERRα mRNA expression was reduced by more than 5-fold, Mfn2 mRNA levels were decreased by 2-fold, and Nrf1 was decreased by 30% in SOD1G86R mice when compared to WT animals at 105 days (Fig5F). In addition, mitochondrial DNA quantification indicated a decreased number of mitochondria in TA of SOD1G86R mice toward the end stage of disease (Fig6A). Interestingly, this decrease in mitochondrial DNA was not observed in the soleus muscle. These data suggest that increased activation of the lipid oxidation pathways in skeletal muscle of SOD1G86R mice occurs independently of PGC-1α and that this metabolic change does not have the support of the mitochondrial machinery of the cell. Presumably, this would have deleterious effects due to accumulation of β-oxidation by-products and ROS (Bonnard et al, 2008). Indeed, glutathione peroxidase 1 (GPX1), an important indicator of oxidative stress, was increased in the TA but not the soleus of SOD1G86R mice at end stage of disease (Fig6B).


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)

Altered mitochondrial function in glycolytic muscle of SOD1G86R miceMitochondrial DNA (mtDNA) was quantified using qPCR. Relative mtDNA levels are expressed as the ratio between mitochondrial-encoded gene Cox1 and the nuclear-encoded gene cyclophilin A. Graphs represent mean fold change ± SEM from age-matched WT for tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. ***P < 0.0001 (n = 5 and 4 for WT and SOD1G86R, respectively, at 65 days; n = 6/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of Gpx1 were measured by qPCR at the indicated ages in tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. ***P < 0.0001 (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 9 and 8 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
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Related In: Results  -  Collection

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fig06: Altered mitochondrial function in glycolytic muscle of SOD1G86R miceMitochondrial DNA (mtDNA) was quantified using qPCR. Relative mtDNA levels are expressed as the ratio between mitochondrial-encoded gene Cox1 and the nuclear-encoded gene cyclophilin A. Graphs represent mean fold change ± SEM from age-matched WT for tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. ***P < 0.0001 (n = 5 and 4 for WT and SOD1G86R, respectively, at 65 days; n = 6/genotype at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).Relative mRNA levels of Gpx1 were measured by qPCR at the indicated ages in tibialis anterior (left panel) and soleus (right panel) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT. ***P < 0.0001 (n = 7 and 8 for WT and SOD1G86R, respectively, at 65 days; n = 9 and 8 for WT and SOD1G86R, respectively, at 105 days, two-way ANOVA followed by Fisher's LSD post hoc test).
Mentions: The processes that promote the mobilization and use of fatty acids for ATP synthesis during moderate exercise are subjected to multiple regulatory steps. Typically, increased oxidative capacity and lipid use in muscle is accompanied by a switch in muscle fiber subtype, a phenomenon that is facilitated by peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis and function (Wu et al, 1999; Lin et al, 2002). We thus analyzed the expression of PGC-1α in the TA of SOD1G86R mice. At 65 days of age, Pgc-1α mRNA and protein levels were similar between SOD1G86R and WT mice (Fig5D and E), whereas they were significantly decreased at 105 days of age in SOD1G86R mice. Importantly, at the end stage of the disease the decrease in PGC-1α protein levels correlated with a decrease in the mRNA expression of the main target genes of PGC-1α pathway, estrogen-related receptor α (ERRα), mitofusin 2 (Mfn2), and nuclear respiratory factor 1 (Nrf1) (Puigserver, 2005; Villena & Kralli, 2008) (Fig5E). ERRα mRNA expression was reduced by more than 5-fold, Mfn2 mRNA levels were decreased by 2-fold, and Nrf1 was decreased by 30% in SOD1G86R mice when compared to WT animals at 105 days (Fig5F). In addition, mitochondrial DNA quantification indicated a decreased number of mitochondria in TA of SOD1G86R mice toward the end stage of disease (Fig6A). Interestingly, this decrease in mitochondrial DNA was not observed in the soleus muscle. These data suggest that increased activation of the lipid oxidation pathways in skeletal muscle of SOD1G86R mice occurs independently of PGC-1α and that this metabolic change does not have the support of the mitochondrial machinery of the cell. Presumably, this would have deleterious effects due to accumulation of β-oxidation by-products and ROS (Bonnard et al, 2008). Indeed, glutathione peroxidase 1 (GPX1), an important indicator of oxidative stress, was increased in the TA but not the soleus of SOD1G86R mice at end stage of disease (Fig6B).

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