Myophosphorylase deficiency, or McArdle disease (glycogen storage disease type V), is the most prevalent metabolic myopathy. It is caused by mutations in the pygm gene, resulting in the loss of the myophosphorylase enzyme, essential for glycogen breakdown in skeletal muscle. Traditionally considered a “pure myopathy,” recent findings suggest cardiac involvement, including hypertrophy and heart failure (HF), though mechanisms remain unclear. HF is characterized by Ca 2+ dyshomeostasis and mitochondrial dysfunction, where excessive mitochondrial Ca 2+ uptake triggers Ca 2+ overload, oxidative stress, and contractile dysfunction. Using a CRISPR/Cas9-generated pygm knockout ( pygm −/− ) rat model, we observed cardiac hypertrophy and fibrosis, indicative of maladaptive remodeling. Preliminary studies indicated an increased mitochondrial Ca 2+ uptake within cardiomyocytes, associated with overexpression of the regulatory subunit MICU1, rather than the pore-forming unit MCU. MICU1 expression is tissue-specific. Importantly, the heart expresses relatively low MICU1 levels, permitting mitochondria to decode rapid cytosolic Ca 2+ oscillations and match energy supply to workload. We hypothesize that an altered MICU1:MCU ratio may reprogram mitochondrial Ca 2+ uptake toward a liver-like phenotype. This phenotype features elevated thresholds at low cytosolic Ca 2+ but excessive uptake during high Ca 2+ transients, leading to Ca 2+ overload, oxidative stress, and cardiac dysfunction. This study explores MICU1-dependent reprogramming of mitochondrial Ca 2+ uptake in McArdle cardiomyopathy. We aim to define the mechanisms underlying MICU1 upregulation in McArdle cardiomyopathy and determine how MICU1 overexpression alters mitochondrial Ca 2+ uptake and drives cardiac dysfunction. We aim to establish a new framework for understanding the pathogenesis of McArdle disease by investigating the novel triadic relationship among glycogen metabolism, mitochondrial Ca 2+ dysregulation, and cardiac dysfunction. Focusing on this pathway may facilitate the development of innovative therapies for McArdle cardiomyopathy and other metabolic disorders associated with mitochondrial Ca 2+ dysregulation.
Assogba et al. (Sun,) studied this question.