Abstract
BackgroundLate-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.HypothesisDrug treatment may compromise muscle strength and physical performance more in older individuals with pre-existing metabolic disorders than normal young ones.MethodsKaletra 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.ResultsKaletra 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.ConclusionLong-term Kaletra intake aggravated abdominal obesity and impaired muscle strength. This effect was worse in older animals than in normal young adults.
Highlights
Successful antiretroviral therapy significantly increases mortality and increasing attention is paid to associated morbidities, such as complaints of weakness and fatigue, which are common complaints in patients chronically taking antiretroviral therapy [1,2,3]
Using the metabolic cage system, we found that Kaletra reduced the nocturnal activity (Figure 1B, left panel) but not diurnal activity
Kaletra did not affect respiration exchange rate. Despite these changes in physical activity and metabolic rate, we found no gross drug effect on body weight and composition measured by in vivo nuclear magnetic resonance (NMR) (Figure 1C)
Summary
Successful antiretroviral therapy significantly increases mortality and increasing attention is paid to associated morbidities, such as complaints of weakness and fatigue, which are common complaints in patients chronically taking antiretroviral therapy [1,2,3] Both viral infection and antiretroviral drugs may contribute to this syndrome. Drug-related insulin resistance, dyslipidemia, and mitochondrial toxicity have been reported in rodents treated with antiretrovirals [4,5,6,7,8,9,10,11,12] Limitations for these studies include exclusive use of healthy young animals and paucity of functional measurements. Hypothesis: Drug treatment may compromise muscle strength and physical performance more in older individuals with pre-existing metabolic disorders than normal young ones
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