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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

Decreased grip strength, increased denervation, and increased expression of denervation and atrophy markers throughout disease progression in SOD1G86R miceGrip test was performed to measure mouse muscle strength at different time points during disease progression. Graph represents the mean of percentage from initial force measured at 11 weeks ± SEM. At 13 weeks, *P = 0.03; at 14 weeks, P = 0.06; at 15 weeks, *P = 0.04 (n = 8 for WT and SOD1G86R, respectively, at 11–15 weeks, two-way ANOVA followed by Fisher's LSD post hoc test).Electromyography (EMG) recordings were performed weekly during disease development, starting from 9 weeks of age. Spontaneous electrical activity was considered as positive EMG only for peak-to-peak amplitudes > 50 μV. Left: The percentage of mice presenting with positive EMG in each age group are represented. Right: Representative examples of negative (EMG−) and positive (EMG+) electromyography profiles (n = 10 for WT and SOD1G86R, respectively, at 9–13 weeks and n = 8 and 7 for WT and SOD1G86R, respectively, at 15 weeks).Relative mRNA levels of denervation markers AChR (subunits α and γ) and MuSK were evaluated by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT (n > 5). ***P-values versus WT: < 0.0001 for AChRα, AChRγ, and MuSK in tibialis anterior; and **P-values versus WT: 0.001 for AChRα, and ***P-values versus WT: 0.0007 for AChRγ, 0.0002 for MuSK in soleus (n=7 and 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).Relative mRNA levels of muscle atrophy markers MuRF1 and Atg-1 were measured by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels). Graphs represent mean fold change ± SEM from age-matched WT. ***P-values versus WT: < 0.0001 for MuRF1 and Atg-1 in tibialis anterior; and **P-values versus WT: 0.007 for MuRF1 and P = 0.006 for Atg-1 in soleus (n = 7 and 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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fig02: Decreased grip strength, increased denervation, and increased expression of denervation and atrophy markers throughout disease progression in SOD1G86R miceGrip test was performed to measure mouse muscle strength at different time points during disease progression. Graph represents the mean of percentage from initial force measured at 11 weeks ± SEM. At 13 weeks, *P = 0.03; at 14 weeks, P = 0.06; at 15 weeks, *P = 0.04 (n = 8 for WT and SOD1G86R, respectively, at 11–15 weeks, two-way ANOVA followed by Fisher's LSD post hoc test).Electromyography (EMG) recordings were performed weekly during disease development, starting from 9 weeks of age. Spontaneous electrical activity was considered as positive EMG only for peak-to-peak amplitudes > 50 μV. Left: The percentage of mice presenting with positive EMG in each age group are represented. Right: Representative examples of negative (EMG−) and positive (EMG+) electromyography profiles (n = 10 for WT and SOD1G86R, respectively, at 9–13 weeks and n = 8 and 7 for WT and SOD1G86R, respectively, at 15 weeks).Relative mRNA levels of denervation markers AChR (subunits α and γ) and MuSK were evaluated by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT (n > 5). ***P-values versus WT: < 0.0001 for AChRα, AChRγ, and MuSK in tibialis anterior; and **P-values versus WT: 0.001 for AChRα, and ***P-values versus WT: 0.0007 for AChRγ, 0.0002 for MuSK in soleus (n=7 and 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).Relative mRNA levels of muscle atrophy markers MuRF1 and Atg-1 were measured by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels). Graphs represent mean fold change ± SEM from age-matched WT. ***P-values versus WT: < 0.0001 for MuRF1 and Atg-1 in tibialis anterior; and **P-values versus WT: 0.007 for MuRF1 and P = 0.006 for Atg-1 in soleus (n = 7 and 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: Given that skeletal muscle possesses the capacity to adapt metabolically to physical and functional challenges (Constable et al, 1987; Bassel-Duby & Olson, 2006), the enhanced aerobic capacity and poor anaerobic capacity of SOD1G86R mice might occur as a consequence of muscle denervation. In this study, we assessed the expression of AChRα and AChRγ, two subunits of the nicotinic acetylcholine receptor, and Musk, a muscle-specific kinase, all of which are rapidly overexpressed after denervation or when muscle electrical activity is absent (Duclert & Changeux, 1995; Valenzuela et al, 1995). However, at 65 days of age SOD1G86R mice did not present with any sign of denervation regardless of the metabolic capacity of muscle; muscle grip strength was comparable to that of WT littermates (Fig2A), EMG profiles were normal (Fig2B), and the mRNA expression of molecular markers of denervation (Fig2C) and atrophy (Fig2D) in glycolytic tibialis anterior (TA) or oxidative soleus muscles was similar to WT levels. By contrast, at 105 days when SOD1G86R mice are paralyzed and grip strength is decreased (Fig2A), all SOD1G86R presented with increased spontaneous activity on their EMG profiles (Fig2B). Moreover, induction of denervation and atrophy markers was more pronounced in the TA than in the soleus (Fig2C and D). These data support previous observations that in ALS, glycolytic muscles are more severely affected by disease pathology than oxidative muscles (Dengler et al, 1990; Frey et al, 2000; Pun et al, 2006). We therefore focused our subsequent analysis on the glycolytic TA.


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)

Decreased grip strength, increased denervation, and increased expression of denervation and atrophy markers throughout disease progression in SOD1G86R miceGrip test was performed to measure mouse muscle strength at different time points during disease progression. Graph represents the mean of percentage from initial force measured at 11 weeks ± SEM. At 13 weeks, *P = 0.03; at 14 weeks, P = 0.06; at 15 weeks, *P = 0.04 (n = 8 for WT and SOD1G86R, respectively, at 11–15 weeks, two-way ANOVA followed by Fisher's LSD post hoc test).Electromyography (EMG) recordings were performed weekly during disease development, starting from 9 weeks of age. Spontaneous electrical activity was considered as positive EMG only for peak-to-peak amplitudes > 50 μV. Left: The percentage of mice presenting with positive EMG in each age group are represented. Right: Representative examples of negative (EMG−) and positive (EMG+) electromyography profiles (n = 10 for WT and SOD1G86R, respectively, at 9–13 weeks and n = 8 and 7 for WT and SOD1G86R, respectively, at 15 weeks).Relative mRNA levels of denervation markers AChR (subunits α and γ) and MuSK were evaluated by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT (n > 5). ***P-values versus WT: < 0.0001 for AChRα, AChRγ, and MuSK in tibialis anterior; and **P-values versus WT: 0.001 for AChRα, and ***P-values versus WT: 0.0007 for AChRγ, 0.0002 for MuSK in soleus (n=7 and 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).Relative mRNA levels of muscle atrophy markers MuRF1 and Atg-1 were measured by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels). Graphs represent mean fold change ± SEM from age-matched WT. ***P-values versus WT: < 0.0001 for MuRF1 and Atg-1 in tibialis anterior; and **P-values versus WT: 0.007 for MuRF1 and P = 0.006 for Atg-1 in soleus (n = 7 and 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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fig02: Decreased grip strength, increased denervation, and increased expression of denervation and atrophy markers throughout disease progression in SOD1G86R miceGrip test was performed to measure mouse muscle strength at different time points during disease progression. Graph represents the mean of percentage from initial force measured at 11 weeks ± SEM. At 13 weeks, *P = 0.03; at 14 weeks, P = 0.06; at 15 weeks, *P = 0.04 (n = 8 for WT and SOD1G86R, respectively, at 11–15 weeks, two-way ANOVA followed by Fisher's LSD post hoc test).Electromyography (EMG) recordings were performed weekly during disease development, starting from 9 weeks of age. Spontaneous electrical activity was considered as positive EMG only for peak-to-peak amplitudes > 50 μV. Left: The percentage of mice presenting with positive EMG in each age group are represented. Right: Representative examples of negative (EMG−) and positive (EMG+) electromyography profiles (n = 10 for WT and SOD1G86R, respectively, at 9–13 weeks and n = 8 and 7 for WT and SOD1G86R, respectively, at 15 weeks).Relative mRNA levels of denervation markers AChR (subunits α and γ) and MuSK were evaluated by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels) of WT and SOD1G86R mice. Graphs represent mean fold change ± SEM from age-matched WT (n > 5). ***P-values versus WT: < 0.0001 for AChRα, AChRγ, and MuSK in tibialis anterior; and **P-values versus WT: 0.001 for AChRα, and ***P-values versus WT: 0.0007 for AChRγ, 0.0002 for MuSK in soleus (n=7 and 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).Relative mRNA levels of muscle atrophy markers MuRF1 and Atg-1 were measured by qPCR at the indicated ages (65 and 105 days) in tibialis anterior (upper panels) and soleus (lower panels). Graphs represent mean fold change ± SEM from age-matched WT. ***P-values versus WT: < 0.0001 for MuRF1 and Atg-1 in tibialis anterior; and **P-values versus WT: 0.007 for MuRF1 and P = 0.006 for Atg-1 in soleus (n = 7 and 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: Given that skeletal muscle possesses the capacity to adapt metabolically to physical and functional challenges (Constable et al, 1987; Bassel-Duby & Olson, 2006), the enhanced aerobic capacity and poor anaerobic capacity of SOD1G86R mice might occur as a consequence of muscle denervation. In this study, we assessed the expression of AChRα and AChRγ, two subunits of the nicotinic acetylcholine receptor, and Musk, a muscle-specific kinase, all of which are rapidly overexpressed after denervation or when muscle electrical activity is absent (Duclert & Changeux, 1995; Valenzuela et al, 1995). However, at 65 days of age SOD1G86R mice did not present with any sign of denervation regardless of the metabolic capacity of muscle; muscle grip strength was comparable to that of WT littermates (Fig2A), EMG profiles were normal (Fig2B), and the mRNA expression of molecular markers of denervation (Fig2C) and atrophy (Fig2D) in glycolytic tibialis anterior (TA) or oxidative soleus muscles was similar to WT levels. By contrast, at 105 days when SOD1G86R mice are paralyzed and grip strength is decreased (Fig2A), all SOD1G86R presented with increased spontaneous activity on their EMG profiles (Fig2B). Moreover, induction of denervation and atrophy markers was more pronounced in the TA than in the soleus (Fig2C and D). These data support previous observations that in ALS, glycolytic muscles are more severely affected by disease pathology than oxidative muscles (Dengler et al, 1990; Frey et al, 2000; Pun et al, 2006). We therefore focused our subsequent analysis on the glycolytic TA.

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