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

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)

 

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.

 

Some quotes from the discussion —