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other·preclinical research, biomedical research, neurology, pediatrics·PMC10046759

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

Biomolecules · 10 authors, 7 centres

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TL;DR

Basal respiration levels in NLSD-M fibroblasts were normalized following triheptanoin treatment.

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Basal respiration levels in NLSD-M fibroblasts were normalized following triheptanoin treatment. Spare respiratory capacity increased in all NLSD-M patients after treatment, indicating an anaplerotic effect through acetyl-CoA and propionyl-CoA replenishing deficient TCA cycle intermediates. Two sibling cell lines with partial ATGL loss-of-function mutations grew faster after short-term treatment, whereas cell lines with frameshift mutations producing no protein showed no benefit. Triheptanoin did not reduce triglyceride accumulation. Limitations include the small sample size inherent to this ultra-rare disease, and the in vitro findings cannot be directly translated to humans.

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preclinical research

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ORIGINAL PAPER

PMC10046759

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients

Biomolecules

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ABSTRACT

Abstract Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi ® ), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies. Keywords: triheptanoin, neutral lipid storage disease type M, NLSD, ATGL, lipid storage myopathy, mitochondrial respiration, glycolysis, anaplerosis, cultured fibroblast

CITATION EXPORT

Nelida Inés Noguera, Daniela Tavian, Corrado Angelini et al.. Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients. Biomolecules. (2023). https://doi.org/10.3390/biom13030452

AUTHORS

10 · 7 CENTRES

Nelida Inés Noguera, Daniela Tavian, Corrado Angelini, Francesca Cortese, Massimiliano Filosto, Matteo Garibaldi, Sara Missaglia, Ariela Smigliani, Alessandra Zaza, Elena Maria Pennisi

1Department of Biomedicine and Prevention, TorVergata University of Rome, 00133 Rome, Italy
2Unit of Neuro-Oncoematologia, Santa Lucia Foundation, IRCCS, 00143 Rome, Italy
3Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Università Cattolica del Sacro Cuore, 20123 Milan, Italy
4Neuromuscular Lab, Department of Neurosciences, University of Padova, 35122 Padova, Italy
5Neuromuscular and Rare Neurological Disease Center, Neurology Unit, San Filippo Neri Hospital, ASL Roma 1, 00135 Rome, Italy
6Department of Clinical and Experimental Sciences, NeMO-Brescia Clinical Center for Neuromuscular Diseases, University of Brescia, 25121 Brescia, Italy
7Neuromuscular and Rare Neurological Disease Centre, Department of Neuroscience, Mental Health, and Sensory Organs (NESMOS), SAPIENZA University of Rome, Sant’Andrea Hospital, 00185 Rome, Italy