Key result
LAMP-2 deficiency in Danon disease drives a cardiomyocyte glycolytic switch and senescence-associated fibroblast stiffness.
Why the study?
Danon disease is a severe X-linked disorder caused by LAMP-2 deficiency with diverse manifestations including cardiomyopathies, prompting investigation of its metabolic landscape.
LAMP-2 deficiency in Danon disease drives a metabolic shift toward glycolysis and senescence, contributing to the loss of cardiac biomechanical competence.
Answers are grounded in this paper and cite their sources.
Multi-omics profiling of Danon disease metabolism is hypothesis-generating; larger prospective studies needed before clinical application.
Danon disease is a severe X-linked disorder caused by deficiency of the lysosome-associated membrane protein-2 (LAMP-2). Clinical manifestations are phenotypically diverse and consist of hypertrophic and dilated cardiomyopathies, skeletal myopathy, retinopathy, and intellectual dysfunction. Here, we investigated the metabolic landscape of Danon disease by applying a multi-omics approach and combined structural and functional readouts provided by Raman and atomic force microscopy. Using these tools, Danon patient-derived cardiac tissue, primary fibroblasts, and human induced pluripotent stem cells differentiated into cardiomyocytes (hiPSC-CMs) were analyzed. Metabolic profiling indicated LAMP-2 deficiency promoted a switch toward glycolysis accompanied by rerouting of tryptophan metabolism. Cardiomyocytes' energetic balance and NAD+/NADH ratio appeared to be maintained despite mitochondrial aging. In turn, metabolic adaption was accompanied by a senescence-associated signature. Similarly, Danon fibroblasts appeared more stress prone and less biomechanically compliant. Overall, shaping of both morphology and metabolism contributed to the loss of cardiac biomechanical competence that characterizes the clinical progression of Danon disease.
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Favero et al. (2020) studied Danon disease. LAMP-2 deficiency vs. Healthy controls was evaluated on Metabolic, transcriptomic, and biomechanical profiling. LAMP-2 deficiency in Danon disease drives a metabolic switch toward glycolysis and altered tryptophan metabolism in cardiomyocytes, alongside increased fibroblast stiffness and a senescence-associated fibrotic signature.
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