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Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice.

ABSTRACT: BACKGROUND:Late-middle age HIV patients are prone to fatigue despite effective viral control by antiretroviral therapies. Rodent models to recapitulate this phenotype are still not available. HYPOTHESIS:Drug treatment may compromise muscle strength and physical performance more in older individuals with pre-existing metabolic disorders than normal young ones. METHODS:Kaletra was given to overweight male mice at late-middle age and normal young adults; both on a rodent diet containing 30% fat calorie. Body composition and grip strength were measured at baseline and after drug treatment. Rota-rod running, insulin and glucose tolerance were measured at the end of the experiment. Drug effect on metabolic activity and spontaneous movements were assessed using the metabolic cage system. Representative muscle and fat tissue were analyzed for protein and mRNA expression. Selected findings were tested using murine C2C12 myotubes. RESULTS:Kaletra reduced grip strength in both young and older mice but impaired rotarod performance only in the old. Spontaneous movements were also reduced in Kaletra-treated old mice. Kaletra reduced IGF-1 expression in all muscle groups tested for the old and in cultured myotubes but to a less extent in the muscle of young animals. Reduced IGF-1 expression correlated with increased expression of muscle-specific atrogene MAFbx and MuRF1. Kaletra also increased abdominal fat mass markedly in the old animals and to a less extend in the young. CONCLUSION:Long-term Kaletra intake aggravated abdominal obesity and impaired muscle strength. This effect was worse in older animals than in normal young adults.

SUBMITTER: Wong S

PROVIDER: S-EPMC4524660 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice.

Wong Siu S Bhasin Shalender S Serra Carlo C Yu Yanan Y Deng Lynn L Guo Wen W

Journal of AIDS & clinical research 20130601

<h4>Background</h4>Late-middle age HIV patients are prone to fatigue despite effective viral control by antiretroviral therapies. Rodent models to recapitulate this phenotype are still not available.<h4>Hypothesis</h4>Drug treatment may compromise muscle strength and physical performance more in older individuals with pre-existing metabolic disorders than normal young ones.<h4>Methods</h4>Kaletra was given to overweight male mice at late-middle age and normal young adults; both on a rodent diet ...[more]

PMID: 26251758

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Project description:Increasing age is accompanied by many changes, including declining functional skeletal muscle health and immune dysfunction. Peripheral blood mononuclear cells (PBMCs) are circulating cells that assemble an immune response, but their whole genome transcriptome has not been studied in the context of age-related muscle health. Consequently, this article explored associations between three muscle variables indicative of functional muscle health - maximum handgrip strength (muscle strength), appendicular skeletal muscle mass index (ASMI, muscle mass), and gait speed (physical performance) - and two groups of bioinformatics-generated PBMC gene expression features (gene expression-estimated leukocyte subset proportions and gene clusters). We analyzed cross-sectional data from 95 home-dwelling healthy women ≥ 70 years, using "cell-type identification by estimating relative subsets of RNA transcripts" (CIBERSORT) to estimate leukocyte subset proportions and "weighted correlation network analysis" (WGCNA) to generate gene clusters. Associations were studied using linear regression models and relevant gene clusters were subjected to gene set enrichment analysis using gene ontology. Gait speed and ASMI associated with CIBERSORT-estimated monocyte proportions (β = - 0.090, 95% CI = (- 0.146, - 0.034), p-value = 0.002 for gait speed, and β = - 0.206, 95% CI = (- 0.385, - 0.028), p-value = 0.024 for ASMI), and gait speed associated with CIBERSORT-estimated M2 macrophage proportions (β = - 0.026, 95% CI = (- 0.043, - 0.008), p-value = 0.004). Furthermore, maximum handgrip strength associated with nine WGCNA gene clusters, enriched in processes related to immune function and skeletal muscle cells (β in the range - 0.007 to 0.008, p-values < 0.05). These results illustrate interactions between skeletal muscle and the immune system, supporting the notion that age-related functional muscle health and the immune system are closely linked.

Dataset Information

Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice.

Publications

Lopinavir/Ritonavir Impairs Physical Strength in Association with Reduced Igf1 Expression in Skeletal Muscle of Older Mice.

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