Lactate-induced mitochondrial magnesium uptake and its metabolic implications in the McArdle disease model

McArdle disease, caused by mutations in the pygm encoding myophosphorylase, impairs muscle glycogenolysis and lactate production during exercise, leading to severe energy deficits. Here, we report that the decreased lactate production in McArdle disease regulates mitochondrial magnesium (mMg²⁺) uptake, with major metabolic consequences in skeletal muscle. Using a CRISPR/Cas9-generated pygm knockout (KO) rat model, we demonstrate that KO rats fail to elevate lactate during static muscle contraction and exhibit diminished mMg²⁺ uptake, disrupted ATP synthesis, and impaired mitochondrial respiration. In vitro, caffeine-stimulated KO myotubes showed preserved Ca²⁺ oscillations but lacked lactate production and mMg²⁺ uptake. Restoration of lactate levels via glucose supplementation rescued mMg²⁺ transport and improved metabolic output. These findings underscore the significance of lactate as a crucial regulator of mMg²⁺ homeostasis and provide valuable mechanistic insights into the metabolic dysfunction observed in McArdle disease.