Adaptive Mechanisms That Preserve Cardiac Function in Mice Without Myoglobin

Abstract

Abstract-Mice lacking myoglobin survive to adulthood and meet the circulatory demands of exercise and pregnancy without cardiac decompensation. In the present study, we show that many myoglobin-deficient embryos die in utero at midgestation with signs of cardiac failure. Fetal mice that survive to gestational day 12.5, however, suffer no subsequent excess mortality. Survival in the absence of myoglobin is associated with increased vascularity and the induction of genes encoding the hypoxia-inducible transcription factors 1␣ and 2, stress proteins such as heat shock protein 27, and vascular endothelial growth factor. These adaptations are evident in late fetal life, persist into adulthood, and are sufficient to maintain normal myocardial oxygen consumption during stressed conditions. These data reveal that myoglobin is necessary to support cardiac function during development, but adaptive responses evoked in some animals can fully compensate for the defect in cellular oxygen transport resulting from the loss of myoglobin.

Hypoxia reprograms calcium signaling and regulates myoglobin expression

“…Previous studies support a role for myoglobin either in facilitated oxygen transport or as a store of oxygen for heart and oxidative skeletal myofibers (6,16,20,34,35,39). These studies suggested that myoglobin functioned in part to alleviate hypoxic stress in the myocyte.…”

“…nuclear factor of activated T cells; calcineurin; skeletal muscle MYOGLOBIN IS A CYTOPLASMIC hemoprotein that is abundantly expressed in heart and oxidative skeletal myofibers. Elegant studies using physiological, biochemical, and spectroscopic analyses support an important role for myoglobin in facilitated oxygen transport, as a reservoir for oxygen and as a scavenger of reactive oxygen species in the mammalian heart and skeletal muscle (6,16,20,34,35,39). Detailed transcriptional analyses have been undertaken to define upstream activation motifs including a CCAC box, A/T element, nuclear factor of activated T cells (NFAT) response element, and E boxes that are necessary for muscle-specific transcription of the myoglobin gene (4,5,21,22).…”

“…Mice lacking myoglobin are viable but mount important cellular and molecular adaptations to offset the loss of myoglobin, including the induction of the hypoxic gene program [i.e., hypoxia-inducible factor (HIF)-1, HIF-2, VEGF, etc.] to augment the delivery of oxygen to the myocytes (17,20,35). These adaptations serve to decrease the diffusion distance for oxygen in order for the mice to maintain normal function.…”

AS160 Regulates Insulin- and Contraction-stimulated Glucose Uptake in Mouse Skeletal Muscle

“…Utilization of direct intramuscular DNA injection in combination with in vivo electroporation allows for local delivery and expression of the target gene without an immune response. Furthermore, this approach temporarily bypasses developmental compensations inherent to other genetic manipulations such as transgenic or knock-out models (26). Because it is limited to the superficial tibialis anterior muscle, isolated skeletal muscle preparations cannot be performed in a complementary manner.…”

Mitochondrial Biogenesis Induced by Exercise and Nutrients: Implication for Performance and Health Benefits

“…The latter function remains a controversial issue regarding in vivo skeletal muscles. The fact is Mb-knockout mice showed no superficial physiological deficits, suggested a reassessment of Mb function in vivo (Flögel et al, 2005;Garry et al, 1998 steepen the partial pressure of O2 (PO2) gradient to the mitochondria, effectively shortening the diffusion path for oxygen (Gödecke et al, 1999;Meeson et al, 2001). Therefore, the contribution of Mb during muscle contraction is still in debate in the last two decades.…”