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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

Schematic representation of the described metabolic imbalance in glycolytic muscle fibers of SOD1G86R miceUnder normal conditions in WT mice, both glucose and lipids enter the cell and are used as cellular fuels. In this situation, both pathways are used and are driven by PDK4 according to needs and fuel availability.In the case of ALS, metabolic flexibility is lost because of chronically increased PDK4 and subsequent inhibition of PDH and PFK1 leading to glycogen accumulation. Increased lipid use through β-oxidation that can only function under aerobic conditions may underlie the greater endurance capacity in SOD1G86R mice. With time, the cell produces more reactive oxygen species, thereby inducing cellular damage.Data information: CD36, CD36 antigen/fatty acid translocase, CPT1, carnitine palmitoyl transferase 1, FAs, fatty acids, FA-CoA, acyl-fatty acids, GLUT4, glucose transporter 4, LPL, lipoprotein lipase, PDH, pyruvate dehydrogenase complex, PDK4, pyruvate dehydrogenase kinase 4, PFK1, phosphofructokinase 1, ROS, reactive oxygen species. Drawing was performed with the website Somersault1824 (http://www.somersault1824.com).
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fig09: Schematic representation of the described metabolic imbalance in glycolytic muscle fibers of SOD1G86R miceUnder normal conditions in WT mice, both glucose and lipids enter the cell and are used as cellular fuels. In this situation, both pathways are used and are driven by PDK4 according to needs and fuel availability.In the case of ALS, metabolic flexibility is lost because of chronically increased PDK4 and subsequent inhibition of PDH and PFK1 leading to glycogen accumulation. Increased lipid use through β-oxidation that can only function under aerobic conditions may underlie the greater endurance capacity in SOD1G86R mice. With time, the cell produces more reactive oxygen species, thereby inducing cellular damage.Data information: CD36, CD36 antigen/fatty acid translocase, CPT1, carnitine palmitoyl transferase 1, FAs, fatty acids, FA-CoA, acyl-fatty acids, GLUT4, glucose transporter 4, LPL, lipoprotein lipase, PDH, pyruvate dehydrogenase complex, PDK4, pyruvate dehydrogenase kinase 4, PFK1, phosphofructokinase 1, ROS, reactive oxygen species. Drawing was performed with the website Somersault1824 (http://www.somersault1824.com).

Mentions: PFK1 is the rate-limiting enzyme of the glycolysis, and an increase in glycogen synthase activity and glycogen accumulation in skeletal muscle is characteristic of a muscle that is subjected to endurance training (Vestergaard, 1999). Thus, the increase in endurance capacity in SOD1G86R mice mirrors a profound alteration of fuel preference in muscle fibers. In accordance with this, we observed a progressive decrease of PFK1 activity, and an increase in glycogen synthase activity and glycogen accumulation in skeletal muscle. The initial decrease in PFK1 activity in SOD1G86R mice may be an adaptive response to the progressive accumulation of pyruvate and increased FA uptake, two well-known potent inhibitors of PFK1 (Massao Hirabara et al, 2003). Furthermore, as the entry of glucose into muscle fibers in ALS mice is not affected early in disease (Dupuis et al, 2004; Smittkamp et al, 2014), our data suggest that glucose is rerouted toward glycogen stores rather than being used as an immediate energy source. By the end stage of disease, reduced activities of PFK1 and glycogen synthase, together with an increase of glycogen stores and reduced levels of pyruvate, demonstrate inhibition of the glycolytic pathway. Collectively, these observations suggest that glycolytic muscle is no longer able to mobilize glycogen stores to produce energy and that the inhibition of glycolysis appears to originate downstream of PFK1 (Fig9).


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)

Schematic representation of the described metabolic imbalance in glycolytic muscle fibers of SOD1G86R miceUnder normal conditions in WT mice, both glucose and lipids enter the cell and are used as cellular fuels. In this situation, both pathways are used and are driven by PDK4 according to needs and fuel availability.In the case of ALS, metabolic flexibility is lost because of chronically increased PDK4 and subsequent inhibition of PDH and PFK1 leading to glycogen accumulation. Increased lipid use through β-oxidation that can only function under aerobic conditions may underlie the greater endurance capacity in SOD1G86R mice. With time, the cell produces more reactive oxygen species, thereby inducing cellular damage.Data information: CD36, CD36 antigen/fatty acid translocase, CPT1, carnitine palmitoyl transferase 1, FAs, fatty acids, FA-CoA, acyl-fatty acids, GLUT4, glucose transporter 4, LPL, lipoprotein lipase, PDH, pyruvate dehydrogenase complex, PDK4, pyruvate dehydrogenase kinase 4, PFK1, phosphofructokinase 1, ROS, reactive oxygen species. Drawing was performed with the website Somersault1824 (http://www.somersault1824.com).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492815&req=5

fig09: Schematic representation of the described metabolic imbalance in glycolytic muscle fibers of SOD1G86R miceUnder normal conditions in WT mice, both glucose and lipids enter the cell and are used as cellular fuels. In this situation, both pathways are used and are driven by PDK4 according to needs and fuel availability.In the case of ALS, metabolic flexibility is lost because of chronically increased PDK4 and subsequent inhibition of PDH and PFK1 leading to glycogen accumulation. Increased lipid use through β-oxidation that can only function under aerobic conditions may underlie the greater endurance capacity in SOD1G86R mice. With time, the cell produces more reactive oxygen species, thereby inducing cellular damage.Data information: CD36, CD36 antigen/fatty acid translocase, CPT1, carnitine palmitoyl transferase 1, FAs, fatty acids, FA-CoA, acyl-fatty acids, GLUT4, glucose transporter 4, LPL, lipoprotein lipase, PDH, pyruvate dehydrogenase complex, PDK4, pyruvate dehydrogenase kinase 4, PFK1, phosphofructokinase 1, ROS, reactive oxygen species. Drawing was performed with the website Somersault1824 (http://www.somersault1824.com).
Mentions: PFK1 is the rate-limiting enzyme of the glycolysis, and an increase in glycogen synthase activity and glycogen accumulation in skeletal muscle is characteristic of a muscle that is subjected to endurance training (Vestergaard, 1999). Thus, the increase in endurance capacity in SOD1G86R mice mirrors a profound alteration of fuel preference in muscle fibers. In accordance with this, we observed a progressive decrease of PFK1 activity, and an increase in glycogen synthase activity and glycogen accumulation in skeletal muscle. The initial decrease in PFK1 activity in SOD1G86R mice may be an adaptive response to the progressive accumulation of pyruvate and increased FA uptake, two well-known potent inhibitors of PFK1 (Massao Hirabara et al, 2003). Furthermore, as the entry of glucose into muscle fibers in ALS mice is not affected early in disease (Dupuis et al, 2004; Smittkamp et al, 2014), our data suggest that glucose is rerouted toward glycogen stores rather than being used as an immediate energy source. By the end stage of disease, reduced activities of PFK1 and glycogen synthase, together with an increase of glycogen stores and reduced levels of pyruvate, demonstrate inhibition of the glycolytic pathway. Collectively, these observations suggest that glycolytic muscle is no longer able to mobilize glycogen stores to produce energy and that the inhibition of glycolysis appears to originate downstream of PFK1 (Fig9).

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