Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites
Mitochondrial health declines with age, and older patients can demonstrate dysfunction in mitochondrial-rich tissues, such as cardiac and skeletal muscle. Aged mitochondria may make older adults more susceptible to adverse drug reactions (ADRs). We assessed mitochondrial metabolic function by measur...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/13/5/671 |
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| author | Jennifer Diaz-Espinosa Kathleen A. Stringer Gus R. Rosania |
| author_facet | Jennifer Diaz-Espinosa Kathleen A. Stringer Gus R. Rosania |
| author_sort | Jennifer Diaz-Espinosa |
| collection | DOAJ |
| description | Mitochondrial health declines with age, and older patients can demonstrate dysfunction in mitochondrial-rich tissues, such as cardiac and skeletal muscle. Aged mitochondria may make older adults more susceptible to adverse drug reactions (ADRs). We assessed mitochondrial metabolic function by measuring two metabolites, l-carnitine and acetylcarnitine, to determine their effectiveness as candidate clinical biomarkers for age-related, drug-induced alterations in mitochondrial metabolism. To study age- and medication-related changes in mitochondrial metabolism, we administered the FDA-approved mitochondriotropic drug, clofazimine (CFZ), or vehicle for 8 weeks to young (4-week-old) and old (61-week-old) male C57BL/6J mice. At the end of treatment, whole blood and cardiac and skeletal muscle were analyzed for l-carnitine, acetylcarnitine, and CFZ levels; muscle function was measured via a treadmill test. No differences were found in blood or cardiac carnitine levels of CFZ-treated mice, but CFZ-treated mice displayed lost body mass and alterations in endurance and levels of skeletal muscle mitochondrial metabolites. These findings demonstrate the age-related susceptibility of the skeletal muscle to mitochondria drug toxicity. Since drug-induced alterations in mitochondrial metabolism in skeletal muscle were not reflected in the blood by l-carnitine or acetylcarnitine levels, drug-induced catabolism and changes in muscle function appear more relevant to stratifying individuals at increased risk for ADRs. |
| first_indexed | 2024-03-11T03:30:04Z |
| format | Article |
| id | doaj.art-21bdc482d9b84b478e84a429576505e0 |
| institution | Directory Open Access Journal |
| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-11T03:30:04Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-21bdc482d9b84b478e84a429576505e02023-11-18T02:26:17ZengMDPI AGMetabolites2218-19892023-05-0113567110.3390/metabo13050671Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial MetabolitesJennifer Diaz-Espinosa0Kathleen A. Stringer1Gus R. Rosania2Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USADepartment of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USAMitochondrial health declines with age, and older patients can demonstrate dysfunction in mitochondrial-rich tissues, such as cardiac and skeletal muscle. Aged mitochondria may make older adults more susceptible to adverse drug reactions (ADRs). We assessed mitochondrial metabolic function by measuring two metabolites, l-carnitine and acetylcarnitine, to determine their effectiveness as candidate clinical biomarkers for age-related, drug-induced alterations in mitochondrial metabolism. To study age- and medication-related changes in mitochondrial metabolism, we administered the FDA-approved mitochondriotropic drug, clofazimine (CFZ), or vehicle for 8 weeks to young (4-week-old) and old (61-week-old) male C57BL/6J mice. At the end of treatment, whole blood and cardiac and skeletal muscle were analyzed for l-carnitine, acetylcarnitine, and CFZ levels; muscle function was measured via a treadmill test. No differences were found in blood or cardiac carnitine levels of CFZ-treated mice, but CFZ-treated mice displayed lost body mass and alterations in endurance and levels of skeletal muscle mitochondrial metabolites. These findings demonstrate the age-related susceptibility of the skeletal muscle to mitochondria drug toxicity. Since drug-induced alterations in mitochondrial metabolism in skeletal muscle were not reflected in the blood by l-carnitine or acetylcarnitine levels, drug-induced catabolism and changes in muscle function appear more relevant to stratifying individuals at increased risk for ADRs.https://www.mdpi.com/2218-1989/13/5/671adverse drug reactionsmitochondrial metabolisml-carnitineacetylcarnitinecardiac muscle |
| spellingShingle | Jennifer Diaz-Espinosa Kathleen A. Stringer Gus R. Rosania Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites Metabolites adverse drug reactions mitochondrial metabolism l-carnitine acetylcarnitine cardiac muscle |
| title | Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites |
| title_full | Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites |
| title_fullStr | Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites |
| title_full_unstemmed | Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites |
| title_short | Clofazimine-Mediated, Age-Related Changes in Skeletal Muscle Mitochondrial Metabolites |
| title_sort | clofazimine mediated age related changes in skeletal muscle mitochondrial metabolites |
| topic | adverse drug reactions mitochondrial metabolism l-carnitine acetylcarnitine cardiac muscle |
| url | https://www.mdpi.com/2218-1989/13/5/671 |
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