Preprint Loss of Skeletal Muscle Pyruvate Dehydrogenase Induces Lactic Acidosis & Adaptive Anaplerotic Compensation, 2023, Gopal et al.

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Loss of Skeletal Muscle Pyruvate Dehydrogenase Induces Lactic Acidosis and Adaptive Anaplerotic Compensation via Pyruvate-Alanine Cycling and Glutaminolysis
Keshav Gopal; Abdualrahman Mohammed Abdualkader; Xiaobei Li; Amanda A. Greenwell; Qutuba G. Karwi; Christina Saed; Golam M. Uddin; Ahmed M. Darwesh; K Lockhart Jamieson; Tariq R. Altamimi; Ryekjang Kim; Farah Eaton; John M. Seubert; Gary D. Lopaschuk; John R. Ussher; Rami Al Batran

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the TCA cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated.

Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvate-alanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes the early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis.

These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders.

Link | PDF (Preprint: BioRxiv)

 

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Posted in relation to Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS (2016).

Wikipedia entry for anapldrotic reactions.

Mouse study, where they completely defunctioned PDH in muscle.

Because global knockout of PDH is embryonically lethal and mice with a skeletal muscle- and heart specific PDH deficiency die within 7 days of weaning, we generated mice with a tamoxifen-inducible skeletal muscle–specific knockout of PDH (PDHSkM-/-)

 

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Some quotes from the discussion —

PDH is a part of the mitochondrial PDH complex that catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA, and links glucose metabolism to the mitochondrial TCA cycle. To explore the significance of PDH in metabolic flexibility, PDH was deliberately removed from skeletal muscle, which is a valuable model for studying metabolic flexibility due to its ability to adapt fuel utilization based on the available fuel sources.

Our findings demonstrate that muscle PDH deletion substantially augments the glycolytic pathway and rewires the generated cytosolic pyruvate away from glucose oxidation to towards lactate production by LDH, a phenomenon that induces severe lactic acidosis and causes premature death at rest and sudden death post-low-intensity exercise in mice lacking muscle PDH under [Low Fat Diet] provision.

In contrast to what was seen with LFD provision, mice lacking muscle PDH that were fed an [High Fat Diet] survived without displaying any noticeable phenotype. Body composition and length remained unchanged between the two genotypes throughout the study. Notably, even under HFD supplementation, muscle PDH deficiency induces hyperlactatemia without any concomitant changes in blood pH levels and glucose concentrations.

At the whole-body level, we observed that muscle PDH deficiency leads to an increase in oxygen consumption and a decrease in RER during the light and dark cycle, suggesting an increased reliance on fatty acid oxidation as an adaptive measure to compensate for decreased glucose oxidation.

Interestingly, despite evidence of increased fatty acid oxidation and CrAT activity under HFD supplementation, obese mice with disrupted muscle PDH showed impairment in exercise performance and flexibility to fully switch to glucose oxidation during higher energy demand, leading to early fatigue. We therefore surmise that deficits in muscle PDH activity induce metabolic inflexibility that manifests when there is a rapid switch between glucose and fatty acid oxidation during the transition from rest to exercise.

Ironically, mice lacking muscle PDH that were fed an [High Fat Diet] survived longer, mainly due to increase in reliance on fatty acid oxidation; however, their exercise performance was compromised.