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Skeletal muscle cellular metabolism in older HIV-infected men.

ABSTRACT: Skeletal muscle mitochondrial dysfunction may contribute to low aerobic capacity. We previously reported 40% lower aerobic capacity in HIV-infected men compared to noninfected age-matched men. The objective of this study was to compare skeletal muscle mitochondrial enzyme activities in HIV-infected men on antiretroviral therapy (55 ± 1 years of age, n = 10 African American men) with age-matched controls (55 ± 1 years of age, n = 8 Caucasian men), and determine their relationship with aerobic capacity. Activity assays for mitochondrial function including enzymes involved in fatty acid activation and oxidation, and oxidative phosphorylation, were performed in homogenates prepared from vastus lateralis muscle. Hydrogen peroxide (H2O2), cardiolipin, and oxidized cardiolipin were also measured. β-hydroxy acyl-CoA dehydrogenase (β-HAD) (38%) and citrate synthase (77%) activities were significantly lower, and H2O2 (1.4-fold) and oxidized cardiolipin (1.8-fold) were significantly higher in HIV-infected men. VO2peak (mL/kg FFM/min) was 33% lower in HIV-infected men and was directly related to β-HAD and citrate synthase activity and inversely related to H2O2 and oxidized cardiolipin. Older HIV-infected men have reduced oxidative enzyme activity and increased oxidative stress compared to age-matched controls. Further research is crucial to determine whether an increase in aerobic capacity by exercise training will be sufficient to restore mitochondrial function in older HIV-infected individuals.

SUBMITTER: Ortmeyer HK

PROVIDER: S-EPMC4873639 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Project description:Context: Although androgen treatment increases muscle mass in HIV-infected men, the underlying mechanisms are poorly understood. Analysis of genome-wide microarray data obtained from skeletal muscle biopsies can be used to profile androgen-regulated pathways. Objective: To identify genes and pathways associated with testosterone treatment and myogenesis in the context of HIV-infected men using genome-wide microarray analysis of skeletal muscle biopsies. Results: A significant weight gain was observed in subjects treated with testosterone compared to placebo (+2.05 kgs and â??1.07 kgs, respectively; P = 0.003) as well as gains in DEXA lean; mass (2.93 kgs vs. 0.35 kgs, respectively; P = 0.003). Microarray expression profiles and RTPCR validation of RNA after 14 days of treatment indicated that several gene sets including; transcriptional control, myogenesis, adipogenesis, insulin signaling, apoptosis, cell cycle, chromatin remodeling, and stress response genes were differentially expressed with testosterone treatment. Protein expression analysis of myogenic differentiation and protein synthesis markers (MyoD, Myogenin, phosphorylated p38 MAPK and phosphorylated AKT) in muscle biopsies and skeletal muscle cells treated with DHT confirmed that testosterone engages; a network of pro-myogenic genes. Conclusions: Testosterone-associated gain in muscle mass in HIV-infected men engaged a network of regulatory pathways involved in broad transcriptional control, myogenesis, insulin signaling, chromatin remodeling, and stress response. Further evaluation of precise signaling intermediates within androgen regulated pathways may help to better define improvements in muscle mass, both in healthy and HIV infected patients. Experiment Overall Design: Design, Setting, and Participants: 44 HIV+ men with weight loss were randomized to receive either 300mg testosterone enanthate or placebo injections IM weekly for 16 weeks. Muscle Experiment Overall Design: biopsies were obtained at baseline and on treatment day 14. A random subset of specimens was chosen for microarray analysis; changes in selected genes were confirmed by reverse transcriptase - polymerase chain reaction (RT-PCR), and western blot analysis. Human skeletal Experiment Overall Design: myogenic precursor cells (SkMCs) were cultured in vitro in the presence of dihydrotestosterone (DHT) to evaluate activation of myogenic protein expression. Experiment Overall Design: Main outcome measures: Relative RNA levels in skeletal muscle biopsies were measured by expression profiling with microarrays and expression levels were validated in samples using quantitative RT-PCR. Further confirmation of changes in key myogenic biomarkers was obtained in DHT treated SkMCs.

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Skeletal muscle cellular metabolism in older HIV-infected men.

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