Exploration of Lipid Metabolism in Relation with Plasma Membrane Properties of Duchenne Muscular Dystrophy Cells: Influence of L-Carnitine

Abstract

Duchenne muscular dystrophy (DMD) arises as a consequence of mutations in the dystrophin gene. Dystrophin is a membrane-spanning protein that connects the cytoskeleton and the basal lamina. The most distinctive features of DMD are a progressive muscular dystrophy, a myofiber degeneration with fibrosis and metabolic alterations such as fatty infiltration, however, little is known on lipid metabolism changes arising in Duchenne patient cells. Our goal was to identify metabolic changes occurring in Duchenne patient cells especially in terms of L-carnitine homeostasis, fatty acid metabolism both at the mitochondrial and peroxisomal level and the consequences on the membrane structure and function. In this paper, we compared the structural and functional characteristics of DMD patient and control cells. Using radiolabeled L-carnitine, we found, in patient muscle cells, a marked decrease in the uptake and the intracellular level of L-carnitine. Associated with this change, a decrease in the mitochondrial metabolism can be seen from the analysis of mRNA encoding for mitochondrial proteins. Probably, associated with these changes in fatty acid metabolism, alterations in the lipid composition of the cells were identified: with an increase in poly unsaturated fatty acids and a decrease in medium chain fatty acids, mono unsaturated fatty acids and in cholesterol contents. Functionally, the membrane of cells lacking dystrophin appeared to be less fluid, as determined at 37°C by fluorescence anisotropy. These changes may, at least in part, be responsible for changes in the phospholipids and cholesterol profile in cell membranes and ultimately may reduce the fluidity of the membrane. A supplementation with L-carnitine partly restored the fatty acid profile by increasing saturated fatty acid content and decreasing the amounts of MUFA, PUFA, VLCFA. L-carnitine supplementation also restored muscle membrane fluidity. This suggests that regulating lipid metabolism in DMD cells may improve the function of cells lacking dystrophin.

Quantitative Proteomic Analysis Reveals Metabolic Alterations, Calcium Dysregulation, and Increased Expression of Extracellular Matrix Proteins in Laminin α2 Chain–deficient Muscle

“…For example, energy metabolism was shown to be affected in mdx myoblasts (61). Despite prevalent metabolic alterations in many muscular dystrophies, it is interesting to note that only few attempts to restore energy metabolism have been made (62), and future efforts should therefore be considered.…”

Improvement of Endurance of DMD Animal Model Using Natural Polyphenols

“…Several works demonstrated that, following supplementation in mdx mice, natural compounds were able to reduce fibrosis [ 22 ] and to ameliorate muscle strength [ 31 ]. Furthermore, they exerted antioxidant activity [ 25 ] and regulated the inflammatory cells [ 32 ] and lipid metabolism [ 33 ]. It is known that ROS could exacerbate muscular damage by oxidizing membrane phospholipids and proteins, thus increasing membrane permeability and leakage [ 56 , 57 ].…”

“…The liquid formulation provides DHA plus derived from purified fish oil, deodorized and scented with lemon, and natural vitamin E. The powder formulation provides curcumin conveyed in phytosomes, coenzyme Q10, acetyl-L-carnitine, green tea extract, extract of Scutellaria , and vitamin C, whose functions in modulating dystrophic phenotype have been described above [ 21 – 23 , 28 , 31 , 33 , 34 , 36 , 38 ]. ProAbe was provided by Ystem (Milan, Italy) in collaboration with U.G.A.…”

“…Similarly, carnitine held much promise in neural disorders, allowing osmoprotection and modulating immune and inflammatory responses [ 32 ]. Several works showed that this compound regulated lipid metabolism in DMD patients, restoring muscle membrane fluidity [ 33 ], decreasing glucose oxidation, and reducing fatty acid [ 34 ]. Following previously published data [ 35 ], Fogagnolo and colleagues demonstrated that mdx mice fed with docosahexaenoic acid (DHA) decreased plasma creatine kinase levels and myonecrosis, reducing inflammatory area and the levels of TNF- α [ 36 ].…”

Paediatric fatty liver disease (PeFLD): All is not NAFLD – Pathophysiological insights and approach to management

“…The altered composition of lipid in cells observed in muscular dystrophy is likely due to decreased physical activity, as well as decreased intracellular carnitine and mitochondrial metabolism. 60 One must keep an open mind as elevated aminotransferases, often due to muscle rather than hepatocyte release, with elevated creatinine phosphokinase, rapid weight gain or microvesicular steatosis on liver biopsy may be the presenting problem. 27,61 Similar findings may be observed in limb-girdle muscular dystrophy.…”