Creatine kinase in ischemic and inflammatory disorders

Abstract

The creatine/phosphocreatine pathway plays a conserved and central role in energy metabolism. Compartmentalization of specific creatine kinase enzymes permits buffering of local high energy phosphates in a thermodynamically favorable manner, enabling both rapid energy storage and energy transfer within the cell. Augmentation of this metabolic pathway by nutritional creatine supplementation has been shown to elicit beneficial effects in a number of diverse pathologies, particularly those that incur tissue ischemia, hypoxia or oxidative stress. In these settings, creatine and phosphocreatine prevent depletion of intracellular ATP and internal acidification, enhance post-ischemic recovery of protein synthesis and promote free radical scavenging and stabilization of cellular membranes. The creatine kinase energy system is itself further regulated by hypoxic signaling, highlighting the existence of endogenous mechanisms in mammals that can enhance creatine metabolism during oxygen deprivation to promote tissue resolution and homeostasis. Here, we review recent insights into the creatine kinase pathway, and provide rationale for dietary creatine supplementation in human ischemic and inflammatory pathologies.

Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism

“…The complex effects of altering these enzymes on cell survival is shown by KCRU overexpression, which enhanced the survival of breast cancer cells, while KCRB KD induced cell death in hypoxic ovarian cancer cells (43). Cr metabolism, which translocates ATP from sites of production to locations of ATP consumption, acts as a spatial/temporal energy buffer utilizing Cr, ATP, and ADP at distinct subcellular compartments (46). Consistent with this, colon cancer cells were shown to secrete KCRB extracellularly to generate and import PCr to enhance energy (19).…”

Efeitos da suplementação com creatina na lesão de isquemia e reperfusão após transplante pulmonar unilateral em ratos

“…O sistema Cr/CK define um importante e altamente conservado circuito fosfato, que promove suporte para a respiração mitocondrial e retorno energético celular por atenuar os desequilíbrios temporais e espaciais na oferta e demanda de ATP (Ellington, 1989;Kitzenberg et al, 2016). Todas as isoenzimas catalisam a transferência reversível da gama-fosfato do ATP para o grupo guanidino da creatina para gerar fosfocreatina e ADP, mediando assim um armazenamento eficiente no citosol de fosfatos de alta energia para o reabastecimento rápido e focal de ATP (Wallimann et al, 1992;Walliman et al, 2011;Kitzenberg et al, 2016).…”

“…Todas as isoenzimas catalisam a transferência reversível da gama-fosfato do ATP para o grupo guanidino da creatina para gerar fosfocreatina e ADP, mediando assim um armazenamento eficiente no citosol de fosfatos de alta energia para o reabastecimento rápido e focal de ATP (Wallimann et al, 1992;Walliman et al, 2011;Kitzenberg et al, 2016).…”

“…De fato, estudos clínicos apontam as propriedades neuroprotetoras da creatina e os efeitos benéficos da fosfocreatina na atenuação do estresse cardiovascular (Kitzenberg et al, 2016). Sendo assim, acreditamos que o uso da creatina na dieta seja um candidato promissor no tratamento profilático independente ou como complemento de terapias convencionais para doenças isquêmicas, ou ainda para procedimentos cirúrgicos que necessitem que algum órgão seja submetido a uma isquemia temporária, como é o caso dos transplantes.…”

Methane bioactivity and interactions with other biological gases

“…The maintenance of physical and immunological barriers between the interior milieu and intestinal lumen is of vital importance, but the intestine is sensitive to hypoxia and the GI system is among the most vulnerable organs during circulatory redistributions (Vajda et al, 2004). Although small fluctuations of metabolites can be compensated by high-energy phosphate systems within the cells of the bowel (Kitzenberg et al, 2016), longer periods of ischemia or ischemia followed by a rapid reestablishment of the blood flow leads to severe damage.…”