Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice.

OBJECTIVE: Lysosomal acid lipase (LAL) is the only enzyme known to hydrolyze cholesteryl esters (CE) and triacylglycerols in lysosomes at an acidic pH. Despite the importance of lysosomal hydrolysis in skeletal muscle (SM), research in this area is limited. We hypothesized that LAL may play an important role in SM development, function, and metabolism as a result of lipid and/or carbohydrate metabolism disruptions. RESULTS: Mice with systemic LAL deficiency (Lal-/-) had markedly lower SM mass, cross-sectional area, and Feret diameter despite unchanged proteolysis or protein synthesis markers in all SM examined. In addition, Lal-/- SM showed increased total cholesterol and CE concentrations, especially during fasting and maturation. Regardless of increased glucose uptake, expression of the slow oxidative fiber marker MYH7 was markedly increased in Lal-/-SM, indicating a fiber switch from glycolytic, fast-twitch fibers to oxidative, slow-twitch fibers. Proteomic analysis of the oxidative and glycolytic parts of the SM confirmed the transition between fast- and slow-twitch fibers, consistent with the decreased Lal-/- muscle size due to the "fiber paradox". Decreased oxidative capacity and ATP concentration were associated with reduced mitochondrial function of Lal-/- SM, particularly affecting oxidative phosphorylation, despite unchanged structure and number of mitochondria. Impairment in muscle function was reflected by increased exhaustion in the treadmill peak effort test in vivo. CONCLUSION: We conclude that whole-body loss of LAL is associated with a profound remodeling of the muscular phenotype, manifested by fiber type switch and a decline in muscle mass, most likely due to dysfunctional mitochondria and impaired energy metabolism, at least in mice.

Association between Serum Free Fatty Acids and Clinical and Laboratory Parameters in Acute Heart Failure Patients.

Very little is known about the association between individual serum free fatty acids (FFAs) and clinical and laboratory parameters (indicators of heart failure severity) in acute heart failure (AHF) patients. Here, the baseline serum levels of FFAs, 16:0 (palmitic acid), 16:1 (palmitoleic acid), 18:0 (stearic acid), 18:1 (oleic acid), 18:2 (linoleic acid), 18:3 (alpha-linolenic acid or gamma-linolenic acid), 20:4 (arachidonic acid), 20:5 (eicosapentaenoic acid), and 22:6 (docosahexaenoic acid), were determined in 304 AHF patients (94.7% belonged to New York Heart Association functional class IV) using gas chromatography. Spearman correlation coefficients were used to examine the associations between the individual and total (the sum of all FFAs) FFAs and clinical and laboratory parameters. After applying a Bonferroni correction to correct for multiple testing, the total FFAs, as well as the individual FFAs (except FFAs 18:0, 20:5, and 22:6), were found to be significantly positively correlated with serum albumin. Only a few additional associations were found: FFA 16:0 was significantly negatively correlated with systolic pulmonary artery pressure, FFA 18:3 was significantly negatively correlated with C-reactive protein and body mass index, and FFA 20:4 was significantly negatively correlated with blood urea nitrogen. Based on our results, we conclude that in patients with severe AHF, individual and total serum FFAs are slightly associated with established laboratory and clinical parameters, which are indicators of heart failure severity.