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

Wong S, Bhasin S, Serra C, Yu Y, Deng L, Guo W - J AIDS Clin Res (2013)

Bottom Line: 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.This effect was worse in older animals than in normal young adults.

View Article: PubMed Central - PubMed

Affiliation: Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of Kaletra on fat tissue mRNA expression(A) Expression of adipocyte transcription factor PPARγ2 and C/EBPα, adiponectin, and TNFalpha in abdominal epididymal (upper panel) and subcutaneous inguinal (lower panel) fat depots. (B) The ratio of mRNA expression between cyclin D1 and cyclin D3 (CCND1/CCND3). All results are normalized to house-keeping gene HPRT, shown as means +/− se. N = 6, Student’s t test.
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Figure 3: Effects of Kaletra on fat tissue mRNA expression(A) Expression of adipocyte transcription factor PPARγ2 and C/EBPα, adiponectin, and TNFalpha in abdominal epididymal (upper panel) and subcutaneous inguinal (lower panel) fat depots. (B) The ratio of mRNA expression between cyclin D1 and cyclin D3 (CCND1/CCND3). All results are normalized to house-keeping gene HPRT, shown as means +/− se. N = 6, Student’s t test.

Mentions: Lopinavir may inhibit adipocyte differentiation in vitro but the in vivo results are inconclusive [19–22,8,9]. As shown in Figure 3A (upper panel), Kaletra did not change inguinal fat expression of (Peroxisome proliferator-activated receptor gamma) PPARγ2 and Ccaat-enhancer-binding proteins (C/EBPα), both are master transcription factors that coordinately regulate adipogenesis [23] or their downstream target adiponectin but reduced expression of inflammatory cytokine TNFα, a cytokine known to inhibit adipogenesis [24]. In epididymal fat, Kaletra moderately increased expression of PPARγ2 and adiponectin and simultaneously reduced expression of TNFα (Figure 3A, lower panel). Together, these results do not suggest Kaletra negatively regulate adipocyte differentiation in vivo. Additionally, Kaletra reduced the ratio of cyclin D1 (CCND1) to cyclin D3 (CCND3) in both inguinal and epididymal fat (Figure 3B). Since D1 is typically found in proliferating cells while D3 is important for fat cell terminal differentiation and maintenance [25–27], a reduction in the D1/D3 ratio suggests that Kaletra promote fat cell differentiation in vivo, which could contribute to explain the marked increase of epididymal fat mass (Figure 2B). Besides, Kaletra-associated reduction in TNFα expression implies that fat tissue inflammation is unlikely a main contributor to the drug-induced loss of in vivo physical and metabolic function.


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

Wong S, Bhasin S, Serra C, Yu Y, Deng L, Guo W - J AIDS Clin Res (2013)

Effects of Kaletra on fat tissue mRNA expression(A) Expression of adipocyte transcription factor PPARγ2 and C/EBPα, adiponectin, and TNFalpha in abdominal epididymal (upper panel) and subcutaneous inguinal (lower panel) fat depots. (B) The ratio of mRNA expression between cyclin D1 and cyclin D3 (CCND1/CCND3). All results are normalized to house-keeping gene HPRT, shown as means +/− se. N = 6, Student’s t test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4524660&req=5

Figure 3: Effects of Kaletra on fat tissue mRNA expression(A) Expression of adipocyte transcription factor PPARγ2 and C/EBPα, adiponectin, and TNFalpha in abdominal epididymal (upper panel) and subcutaneous inguinal (lower panel) fat depots. (B) The ratio of mRNA expression between cyclin D1 and cyclin D3 (CCND1/CCND3). All results are normalized to house-keeping gene HPRT, shown as means +/− se. N = 6, Student’s t test.
Mentions: Lopinavir may inhibit adipocyte differentiation in vitro but the in vivo results are inconclusive [19–22,8,9]. As shown in Figure 3A (upper panel), Kaletra did not change inguinal fat expression of (Peroxisome proliferator-activated receptor gamma) PPARγ2 and Ccaat-enhancer-binding proteins (C/EBPα), both are master transcription factors that coordinately regulate adipogenesis [23] or their downstream target adiponectin but reduced expression of inflammatory cytokine TNFα, a cytokine known to inhibit adipogenesis [24]. In epididymal fat, Kaletra moderately increased expression of PPARγ2 and adiponectin and simultaneously reduced expression of TNFα (Figure 3A, lower panel). Together, these results do not suggest Kaletra negatively regulate adipocyte differentiation in vivo. Additionally, Kaletra reduced the ratio of cyclin D1 (CCND1) to cyclin D3 (CCND3) in both inguinal and epididymal fat (Figure 3B). Since D1 is typically found in proliferating cells while D3 is important for fat cell terminal differentiation and maintenance [25–27], a reduction in the D1/D3 ratio suggests that Kaletra promote fat cell differentiation in vivo, which could contribute to explain the marked increase of epididymal fat mass (Figure 2B). Besides, Kaletra-associated reduction in TNFα expression implies that fat tissue inflammation is unlikely a main contributor to the drug-induced loss of in vivo physical and metabolic function.

Bottom Line: 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.This effect was worse in older animals than in normal young adults.

View Article: PubMed Central - PubMed

Affiliation: Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, USA.

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.

No MeSH data available.


Related in: MedlinePlus