Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Akhmetshina, A.
Role of lysosomal acid lipase in skeletal muscle formation, metabolism, and functions
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 153
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kratky Dagmar
- Schoiswohl Gabriele Maria
- Altmetrics:
- Abstract:
- Lysosomal acid lipase (LAL) hydrolyzes triglycerides (TG) and cholesteryl esters (CE) within lysosomes of multiple cells and tissues at an acidic pH. Despite a number of studies dealing with lysosomal function in skeletal muscle (SM), lipid hydrolysis by LAL in lysosomes of SM has not been well characterized. Recent data suggested that LAL may play an important role in SM development, function, and metabolism as a result of impaired lipid and/or carbohydrate metabolism. SM mass, cross-sectional area, and the Feret diameter were markedly lower in mice with systemic LAL deficiency (Lal-/-), despite no evidence of proteolysis or impaired protein synthesis in all SM examined. In addition, we observed elevated CE concentration and impaired metabolic profile in all investigated SM samples, especially during fasting. Untargeted proteomic profiling of oxidative and glycolytic fibers of SM revealed upregulation of proteins associated with the transition between fast and slow fibers. In addition, we found significantly increased MyHCI expression in Lal-/- SM, which is specific for slow oxidative fibers. Gene ontology enrichment analysis indicated reduced mitochondrial function and impaired organization, particularly affecting oxidative phosphorylation, in Lal-/- SM, consistent with decreased oxidative capacity and ATP concentration. Similar to our mouse model, C2C12 myoblasts treated with the LAL inhibitor Lalistat-2 and primary myoblasts isolated from Lal-/- mice in complete growth medium showed increased levels of CE. Myofiber formation, however, was comparable in both in vitro models studied. Moreover, we were unable to detect any changes in mitochondrial function upon Lalistat-2 treatment of C2C12 cells or primary myoblasts derived from Lal-/-. Taken together, loss of LAL is associated with increased expression of slow oxidative fibers in SM, impaired mitochondrial function and muscle metabolism, but only in knockout mice in vivo and not ex vivo. The aforementioned changes, with the exception of increased CE levels, were not confirmed in the studied cell models with reduced LAL activity. The differences we found between in vivo and ex vivo/in vitro models are possibly related to nutrient unavailability and systemic inflammation in Lal-/- mice.