Abstract
Continuous contractile activity of the heart is essential and the required energy is mostly provided by fatty acid (FA) oxidation. Myocardial lipid accumulation can lead to pathological responses, however the underlying mechanisms remain elusive. The role of myoglobin in dioxygen binding in cardiomyocytes and oxidative skeletal muscle has widely been appreciated. Our recent work established myoglobin as a protector of cardiac function in hypoxia and disease states. We here unravel a novel role of cardiac myoglobin in governing FA metabolism to ensure the physiological energy production through β-oxidation, preventing myocardial lipid accumulation and preserving cardiac functions. In vivo1H magnetic resonance spectroscopy unveils a 3-fold higher deposition of lipids in mouse hearts lacking myoglobin, which was associated with depressed cardiac function compared to wild-type hearts as assessed by echocardiography. Mass spectrometry reveals a marked increase in tissue triglycerides with preferential incorporation of palmitic and oleic acids. Phospholipid levels as well as the metabolome, transcriptome and proteome related to FA metabolism tend to be unaffected by myoglobin ablation. Our results reveal a physiological role of myoglobin in FA metabolism with the lipid accumulation-suppressing effects of myoglobin preventing cardiac lipotoxicity.
Highlights
Myoglobin, a member of the heme globin family, is a multifunctional protein playing a critical role in biological processes, protecting the cardiovascular system[1]
Representative water-suppressed 1H magnetic resonance (MR) spectra are illustrated in Fig. 1c for each genotype, where resonances for creatine, taurine, choline and several signals originating from lipids can be unequivocally resolved
Quantification of the spectra revealed that Mb−/− hearts are characterized by a threefold higher lipid content compared to WT mouse hearts (5.5% ± 1.5% vs. 1.8% ± 0.7% of 1H magnetic resonance spectroscopy (1H MRS) water signal, p = 0.034; Fig. 1c,d)
Summary
A member of the heme globin family, is a multifunctional protein playing a critical role in biological processes, protecting the cardiovascular system[1]. A few triglyceride stores serve as temporary endogenous source of FAs and exhibit a dynamic nature with a short mean turnover time[12,14,15] This fine tuned FA metabolism by a balanced uptake and oxidation is absolutely necessary for covering cardiac energy requirement, preserving normal heart function and preventing lipid accumulation. Recent experimental and clinical studies using 1H magnetic resonance spectroscopy (1H MRS) indicated that perturbation of this homeostasis leads to cardiac dysfunction caused or aggravated by myocardial lipid deposition, a process termed cardiac lipotoxicity[16,17,18,19] These studies provided evidence that failure of intracellular triglyceride-derived FAs mobilization induces triglyceride accumulation. These findings point to a physiological role of myoglobin in FA metabolism
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