Alcohol-Mediated Dysregulation of Mitochondrial Protein Expression in Skeletal Muscle of SIV-Infected Female Rhesus Macaques
Publication Date
July 2019
Location
LSU Health Medical Education Building
Document Type
Abstract
Start Date
26-7-2019 9:00 AM
End Date
26-7-2019 12:00 PM
Description
Rates of heavy drinking in people living with human immunodeficiency virus (PLWH) is almost twice that found in the non-HIV-infected population. At-risk alcohol use in PLWH disrupts skeletal muscle regulation, which is the major metabolic tissue regulating whole-body energy homeostasis. Mitochondria are essential for skeletal muscle metabolic health. As people are living longer with HIV due to antiretroviral therapy (ART), age-related comorbidities are increasing in PLWH including insulin resistance and cardiometabolic risk. One mechanism contributing to these comorbidities is mitochondrial dysfunction. Proteins implicated in mitochondrial biogenesis and function are peroxisome proliferated-activated receptor (PPAR) gamma coactivator (PGC)-1α, PGC-1β, PPARα, and mitochondrial transcription factor A (TFAM). PGC-1α and PGC-1β are transcriptional coactivators considered master regulators of mitochondrial biogenesis, PPARα is a transcription factor for fatty acid oxidation enzymes, and TFAM is a mitochondrial transcription factor. Previous work has shown that chronic binge alcohol (CBA) dysregulates expression of genes implicated in mitochondrial function in skeletal muscle of SIV-infected female rhesus macaques. CBA decreased PGC-1β and TFAM expression, increased PPARα expression, and did not change PGC-1α expression. This led to the hypothesis that CBA similarly alters mitochondrial protein expression in skeletal muscle of SIV-infected, ART-treated female rhesus macaques. Macaques (N=10) were administered a daily binge dose of alcohol (CBA, 13- 15g/kg/week) or isovolumetric water (VEH) for three months prior to SIV infection and throughout the duration of the study. ART administration was initiated 2.5 months after SIV infection. At study endpoint (approximately 12 months post-SIV infection), skeletal muscle tissue was collected and homogenized. Cytosolic and nuclear-enriched protein fractions were extracted, and Western blotting was performed to determine expression of PGC-1α, PGC-1β, PPARα, and TFAM. There was a trend (p=0.056) for CBA to increase PPARα protein expression in the nuclear fraction, but no other CBA-mediated differences were observed. Decreased gene expression of PGC-1β with no change in protein expression indicate the potential for post-translational modifications. The increase in nuclear expression of PPARα could indicate increased reliance on fatty acid oxidation to meet skeletal muscle energetic demands. Future directions include analysis of CBA-mediated post-translational modifications to PGC-1 β (e.g., acetylation) that could alter its activity and measurement of expression of proteins downstream of PPARα.
Recommended Citation
Elnaggar, Jasmin E., "Alcohol-Mediated Dysregulation of Mitochondrial Protein Expression in Skeletal Muscle of SIV-Infected Female Rhesus Macaques" (2019). Summer Research Internship Program. 2.
https://digitalscholar.lsuhsc.edu/srip/2019/hs/2
Alcohol-Mediated Dysregulation of Mitochondrial Protein Expression in Skeletal Muscle of SIV-Infected Female Rhesus Macaques
LSU Health Medical Education Building
Rates of heavy drinking in people living with human immunodeficiency virus (PLWH) is almost twice that found in the non-HIV-infected population. At-risk alcohol use in PLWH disrupts skeletal muscle regulation, which is the major metabolic tissue regulating whole-body energy homeostasis. Mitochondria are essential for skeletal muscle metabolic health. As people are living longer with HIV due to antiretroviral therapy (ART), age-related comorbidities are increasing in PLWH including insulin resistance and cardiometabolic risk. One mechanism contributing to these comorbidities is mitochondrial dysfunction. Proteins implicated in mitochondrial biogenesis and function are peroxisome proliferated-activated receptor (PPAR) gamma coactivator (PGC)-1α, PGC-1β, PPARα, and mitochondrial transcription factor A (TFAM). PGC-1α and PGC-1β are transcriptional coactivators considered master regulators of mitochondrial biogenesis, PPARα is a transcription factor for fatty acid oxidation enzymes, and TFAM is a mitochondrial transcription factor. Previous work has shown that chronic binge alcohol (CBA) dysregulates expression of genes implicated in mitochondrial function in skeletal muscle of SIV-infected female rhesus macaques. CBA decreased PGC-1β and TFAM expression, increased PPARα expression, and did not change PGC-1α expression. This led to the hypothesis that CBA similarly alters mitochondrial protein expression in skeletal muscle of SIV-infected, ART-treated female rhesus macaques. Macaques (N=10) were administered a daily binge dose of alcohol (CBA, 13- 15g/kg/week) or isovolumetric water (VEH) for three months prior to SIV infection and throughout the duration of the study. ART administration was initiated 2.5 months after SIV infection. At study endpoint (approximately 12 months post-SIV infection), skeletal muscle tissue was collected and homogenized. Cytosolic and nuclear-enriched protein fractions were extracted, and Western blotting was performed to determine expression of PGC-1α, PGC-1β, PPARα, and TFAM. There was a trend (p=0.056) for CBA to increase PPARα protein expression in the nuclear fraction, but no other CBA-mediated differences were observed. Decreased gene expression of PGC-1β with no change in protein expression indicate the potential for post-translational modifications. The increase in nuclear expression of PPARα could indicate increased reliance on fatty acid oxidation to meet skeletal muscle energetic demands. Future directions include analysis of CBA-mediated post-translational modifications to PGC-1 β (e.g., acetylation) that could alter its activity and measurement of expression of proteins downstream of PPARα.
Comments
Mentors: Dr. Levitt and Dr. Simon