PYGM Protects Against Myocardial Infarction by Enhancing Glycogenolysis and Facilitating Autophagic Flux

PYGM (muscle glycogen phosphorylase), the rate-limiting enzyme in glycogenolysis, plays an indispensable role in maintaining cardiac energy metabolism. However, the role of PYGM in the pathogenesis of myocardial infarction (MI) remains unclear.

The expression profiles of PYGM in cardiac tissues and plasma samples from subjects with MI were assessed using immunoblotting. The role of PYGM in MI was determined by evaluating the effects of PYGM deficiency and its replenishment through adeno-associated virus-mediated PYGM expression in mice with MI.

We found that circulating PYGM levels and their cardiac contents were significantly decreased in patients with MI, which was associated with impaired cardiac function. Loss of PYGM significantly exacerbated MI-induced cardiac dysfunction and damage in mice, and replenishment of PYGM profoundly reversed these adverse effects. Mechanistically, PYGM enhanced glycogenolysis by activating glycolysis and the pentose phosphate pathway, thereby improving cardiac energy homeostasis and mitigating oxidative stress. In addition, PYGM improved MI-induced autophagic flux obstacles and alleviated MI-induced cardiac damage by suppressing the expression of Thbs1 (thrombospondin-1). Moreover, genetic deficiency or pharmacological blockage of autophagy attenuated the protective effects of PYGM against MI-induced cardiac injury, and cardiac-specific knockdown of Thbs1 substantially improved the adverse impact of MI on cardiac dysfunction and damage in PYGM-null mice.

PYGM safeguards against MI-induced myocardial injury by stimulating glycogenolysis and promoting autophagic flux, thus preserving myocardial energy homeostasis.