Lifelong creatine deficiency leads to augmented sarcoplasmic reticulum calcium release but not heart failure

Creatine kinase (CK) is considered a crucial energy transfer system in cardiac muscle. Some studies have suggested that reduced CK energy transfer in the heart causes energy starvation, limits cardiac performance, and ultimately leads to heart failure. In agreement with this hypothesis, the hearts from creatine-deficient mice lacking arginine:glycine amidinotransferase (AGAT KO) have been shown, in some experiments, to resemble failing hearts. However, it is unclear if AGAT KO induces changes in cardiomyocyte substructure and Ca²⁺ cycling that resemble heart failure, including impairment of sarcoplasmic reticulum (SR) Ca²⁺ release and reuptake. To investigate this, we assessed functional and structural aspects of Ca²⁺ handling in cardiomyocytes from KO and WT littermates. We found minor, sex-dependent differences in the organization of transverse tubules and ryanodine receptors (RyRs), no differences in the expression and relative phosphorylation of RyR and PLB, but higher S100A1 expression levels. AGAT KO cardiomyocytes exhibited larger and longer Ca²⁺ transients with the same decay rate as WT. Ca²⁺ spark frequency and SR Ca²⁺ content were also increased in KO, while sodium-calcium exchanger activity was unchanged. Thus, our results strongly suggest that SR Ca²⁺ cycling is augmented in AGAT KO hearts. Although AGAT KO hearts also exhibited increased AMPK activation, suggesting higher levels of AMP/ADP, this did not detectably impair sarcoendoplasmic reticulum Ca²⁺-ATPase activity. In conclusion, the changes in AGAT KO cardiomyocytes are opposite to those in failing cardiomyocytes, showing that lifelong absence of CK energy transfer does not lead to heart failure.<b>NEW & NOTEWORTHY</b> Previous studies have suggested that reduced creatine kinase (CK) activity may lead to heart failure. Here, we studied calcium handling in the hearts of creatine-deficient arginine-glycine amidino-transferase knockout (AGAT KO) mice with lifelong inhibition of CK. In contrast to failing cardiomyocytes, AGAT KO cardiomyocytes exhibited larger calcium transients due to more readily firing RyR clusters releasing more calcium from the SR. Thus, lifelong creatine deficiency does not lead to the phenotype observed in heart failure.