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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

65-day-old SOD1G86R mice have improved performance during endurance exerciseA–F (A–C) Exercise performance on a treadmill apparatus using an intense exercise (incremental speed paradigm) that relies solely on anaerobic metabolism. (D–F) Exercise performance on a treadmill apparatus using a moderate exercise (constant sub-maximal speed) that relies on the recruitment of aerobic metabolism and that is representative of endurance exercise. (A, D) Kaplan–Meier curves representing values corresponding to the percentage of mice still running at a given time point. (B, E) Median values of the time that mice ran are represented in the min to max graphical representation; 15.5 min for wild-type (WT) and 14.33 min for SOD1G86R in (B); 59.33 min for WT and 65.43 min for SOD1G86R in (E). (C, F) Mean distance run ± SEM by WT and SOD1G86R mice in (C) and by WT and SOD1G86R mice in (F).Data information: G86R versus WT, P = 0.017 in (A), **P = 0.0078 in (B), **P = 0.008 in (C) and P = 0.036 in (D) (Mantel–Cox test), **P = 0.0078 in (E), and **P = 0.0061 in (F) (Student's t-test), n = 10 and 13 for WT and SOD1G86R, respectively.
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fig01: 65-day-old SOD1G86R mice have improved performance during endurance exerciseA–F (A–C) Exercise performance on a treadmill apparatus using an intense exercise (incremental speed paradigm) that relies solely on anaerobic metabolism. (D–F) Exercise performance on a treadmill apparatus using a moderate exercise (constant sub-maximal speed) that relies on the recruitment of aerobic metabolism and that is representative of endurance exercise. (A, D) Kaplan–Meier curves representing values corresponding to the percentage of mice still running at a given time point. (B, E) Median values of the time that mice ran are represented in the min to max graphical representation; 15.5 min for wild-type (WT) and 14.33 min for SOD1G86R in (B); 59.33 min for WT and 65.43 min for SOD1G86R in (E). (C, F) Mean distance run ± SEM by WT and SOD1G86R mice in (C) and by WT and SOD1G86R mice in (F).Data information: G86R versus WT, P = 0.017 in (A), **P = 0.0078 in (B), **P = 0.008 in (C) and P = 0.036 in (D) (Mantel–Cox test), **P = 0.0078 in (E), and **P = 0.0061 in (F) (Student's t-test), n = 10 and 13 for WT and SOD1G86R, respectively.

Mentions: During ALS disease progression, a progressive shift in skeletal muscle fiber subtype from fast twitch to slow twitch would presumably result in a concomitant shift toward more oxidative metabolism (Dengler et al, 1990; Frey et al, 2000; Pun et al, 2006; Deforges et al, 2009). Thus, we aimed to determine whether SOD1G86R mice would have improved capacity to support endurance exercise. We compared anaerobic versus aerobic capacities of 65-day-old asymptomatic SOD1G86R mice using two exercise paradigms on a treadmill apparatus: an intense anaerobic exercise that recruits glycolytic fast-twitch fibers (Fig1A–C) and a low-intensity endurance exercise that mobilizes slow-twitch oxidative muscle fibers (Fig1D–F). As shown in Fig1A, when treadmill speed was progressively increased in the intense anaerobic exercise paradigm, 65-day-old SOD1G86R mice had significantly poorer performance than their WT littermates; SOD1G86R mice ran on the treadmill for an average of 13.50 min (median at 14.33), while their WT littermates spent an average of 15.78 min (median at 15.50) on the treadmill (Fig1B). Accordingly, SOD1G86R mice ran a total distance that was 17.6% shorter than the distance covered by their WT littermates (Fig1C). By contrast, when challenged with a moderate exercise paradigm that is representative of an endurance workout (Fig1D–F), SOD1G86R mice proved to have significantly greater endurance than their WT littermates (Fig1D). In response to moderate exercise, SOD1G86R mice ran an average of 67.34 min (median at 65.43) before reaching exhaustion, while their WT littermates ran an average of 46.10 min (median at 59.33) prior to exhaustion (Fig1D). Indeed, the resistance of SOD1G86R mice to reach exhaustion when subjected to this exercise paradigm resulted in them running a total distance that was 36% greater than the distance covered by their WT littermates (Fig1E).


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)

65-day-old SOD1G86R mice have improved performance during endurance exerciseA–F (A–C) Exercise performance on a treadmill apparatus using an intense exercise (incremental speed paradigm) that relies solely on anaerobic metabolism. (D–F) Exercise performance on a treadmill apparatus using a moderate exercise (constant sub-maximal speed) that relies on the recruitment of aerobic metabolism and that is representative of endurance exercise. (A, D) Kaplan–Meier curves representing values corresponding to the percentage of mice still running at a given time point. (B, E) Median values of the time that mice ran are represented in the min to max graphical representation; 15.5 min for wild-type (WT) and 14.33 min for SOD1G86R in (B); 59.33 min for WT and 65.43 min for SOD1G86R in (E). (C, F) Mean distance run ± SEM by WT and SOD1G86R mice in (C) and by WT and SOD1G86R mice in (F).Data information: G86R versus WT, P = 0.017 in (A), **P = 0.0078 in (B), **P = 0.008 in (C) and P = 0.036 in (D) (Mantel–Cox test), **P = 0.0078 in (E), and **P = 0.0061 in (F) (Student's t-test), n = 10 and 13 for WT and SOD1G86R, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4492815&req=5

fig01: 65-day-old SOD1G86R mice have improved performance during endurance exerciseA–F (A–C) Exercise performance on a treadmill apparatus using an intense exercise (incremental speed paradigm) that relies solely on anaerobic metabolism. (D–F) Exercise performance on a treadmill apparatus using a moderate exercise (constant sub-maximal speed) that relies on the recruitment of aerobic metabolism and that is representative of endurance exercise. (A, D) Kaplan–Meier curves representing values corresponding to the percentage of mice still running at a given time point. (B, E) Median values of the time that mice ran are represented in the min to max graphical representation; 15.5 min for wild-type (WT) and 14.33 min for SOD1G86R in (B); 59.33 min for WT and 65.43 min for SOD1G86R in (E). (C, F) Mean distance run ± SEM by WT and SOD1G86R mice in (C) and by WT and SOD1G86R mice in (F).Data information: G86R versus WT, P = 0.017 in (A), **P = 0.0078 in (B), **P = 0.008 in (C) and P = 0.036 in (D) (Mantel–Cox test), **P = 0.0078 in (E), and **P = 0.0061 in (F) (Student's t-test), n = 10 and 13 for WT and SOD1G86R, respectively.
Mentions: During ALS disease progression, a progressive shift in skeletal muscle fiber subtype from fast twitch to slow twitch would presumably result in a concomitant shift toward more oxidative metabolism (Dengler et al, 1990; Frey et al, 2000; Pun et al, 2006; Deforges et al, 2009). Thus, we aimed to determine whether SOD1G86R mice would have improved capacity to support endurance exercise. We compared anaerobic versus aerobic capacities of 65-day-old asymptomatic SOD1G86R mice using two exercise paradigms on a treadmill apparatus: an intense anaerobic exercise that recruits glycolytic fast-twitch fibers (Fig1A–C) and a low-intensity endurance exercise that mobilizes slow-twitch oxidative muscle fibers (Fig1D–F). As shown in Fig1A, when treadmill speed was progressively increased in the intense anaerobic exercise paradigm, 65-day-old SOD1G86R mice had significantly poorer performance than their WT littermates; SOD1G86R mice ran on the treadmill for an average of 13.50 min (median at 14.33), while their WT littermates spent an average of 15.78 min (median at 15.50) on the treadmill (Fig1B). Accordingly, SOD1G86R mice ran a total distance that was 17.6% shorter than the distance covered by their WT littermates (Fig1C). By contrast, when challenged with a moderate exercise paradigm that is representative of an endurance workout (Fig1D–F), SOD1G86R mice proved to have significantly greater endurance than their WT littermates (Fig1D). In response to moderate exercise, SOD1G86R mice ran an average of 67.34 min (median at 65.43) before reaching exhaustion, while their WT littermates ran an average of 46.10 min (median at 59.33) prior to exhaustion (Fig1D). Indeed, the resistance of SOD1G86R mice to reach exhaustion when subjected to this exercise paradigm resulted in them running a total distance that was 36% greater than the distance covered by their WT littermates (Fig1E).

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