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 impor...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-01-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221287782300203X |
| _version_ | 1797342220472287232 |
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| author | Alena Akhmetshina Valentina Bianco Ivan Bradić Melanie Korbelius Anita Pirchheim Katharina B. Kuentzel Thomas O. Eichmann Helga Hinteregger Dagmar Kolb Hansjoerg Habisch Laura Liesinger Tobias Madl Wolfgang Sattler Branislav Radović Simon Sedej Ruth Birner-Gruenberger Nemanja Vujić Dagmar Kratky |
| author_facet | Alena Akhmetshina Valentina Bianco Ivan Bradić Melanie Korbelius Anita Pirchheim Katharina B. Kuentzel Thomas O. Eichmann Helga Hinteregger Dagmar Kolb Hansjoerg Habisch Laura Liesinger Tobias Madl Wolfgang Sattler Branislav Radović Simon Sedej Ruth Birner-Gruenberger Nemanja Vujić Dagmar Kratky |
| author_sort | Alena Akhmetshina |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T10:30:08Z |
| format | Article |
| id | doaj.art-121b95e681f74b8e83bd5774d9dcc210 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-03-08T10:30:08Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-121b95e681f74b8e83bd5774d9dcc2102024-01-27T06:54:40ZengElsevierMolecular Metabolism2212-87782024-01-0179101869Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of miceAlena Akhmetshina0Valentina Bianco1Ivan Bradić2Melanie Korbelius3Anita Pirchheim4Katharina B. Kuentzel5Thomas O. Eichmann6Helga Hinteregger7Dagmar Kolb8Hansjoerg Habisch9Laura Liesinger10Tobias Madl11Wolfgang Sattler12Branislav Radović13Simon Sedej14Ruth Birner-Gruenberger15Nemanja Vujić16Dagmar Kratky17Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria; Department of Biomedical Science, University of Copenhagen, Copenhagen, DenmarkInstitute of Molecular Biosciences, University of Graz, Graz, Austria; Core Facility Mass Spectrometry, Center for Medical Research, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaBioTechMed-Graz, Graz, Austria; Core Facility Ultrastructural Analysis, Medical University of Graz, Graz, Austria; Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaInstitute of Chemical Technologies and Analytics, TU Wien, Vienna, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaBioTechMed-Graz, Graz, Austria; Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Graz, Austria; Institute of Physiology, Faculty of Medicine, University of Maribor, SloveniaBioTechMed-Graz, Graz, Austria; Institute of Chemical Technologies and Analytics, TU Wien, Vienna, Austria; Diagnostic and Research Institute of Pathology, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, AustriaGottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria; Corresponding author. Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstrasse 6/4, 8010 Graz, Austria.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.http://www.sciencedirect.com/science/article/pii/S221287782300203XLALLAL deficiencyLal-deficient mouseEnergy metabolismMuscle proteomics |
| spellingShingle | Alena Akhmetshina Valentina Bianco Ivan Bradić Melanie Korbelius Anita Pirchheim Katharina B. Kuentzel Thomas O. Eichmann Helga Hinteregger Dagmar Kolb Hansjoerg Habisch Laura Liesinger Tobias Madl Wolfgang Sattler Branislav Radović Simon Sedej Ruth Birner-Gruenberger Nemanja Vujić Dagmar Kratky Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice Molecular Metabolism LAL LAL deficiency Lal-deficient mouse Energy metabolism Muscle proteomics |
| title | Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice |
| title_full | Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice |
| title_fullStr | Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice |
| title_full_unstemmed | Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice |
| title_short | Loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice |
| title_sort | loss of lysosomal acid lipase results in mitochondrial dysfunction and fiber switch in skeletal muscles of mice |
| topic | LAL LAL deficiency Lal-deficient mouse Energy metabolism Muscle proteomics |
| url | http://www.sciencedirect.com/science/article/pii/S221287782300203X |
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