Effect of HIV-1-related protein expression on cardiac and skeletal muscles from transgenic rats

Otis, Jeffrey S.; Ashikhmin, Y.; Brown, Lou Ann S.; Guidot, David M.

doi:10.1186/1742-6405-5-8

Cited by 44 publications

(66 citation statements)

References 30 publications

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“…Our data indicate the presence of cardiomyopathy in the HIV-1 Tg rat, as evidenced by the reduction in myocardial mass, which could not be attributed to the decreased food intake or a reduction in the rate of cardiac protein synthesis. Therefore, these data suggest an enhanced rate of protein degradation in the heart, which is consistent with the previously reported increased mRNA expression of atrogin-1 and MuRF1 in HIV-1 Tg rats (35). Moreover, echocardiography revealed that the loss of cardiac mass in HIV-1 Tg rats was associated with changes in cardiac structure and function.…”

Section: Discussionsupporting

confidence: 80%

“…Moreover, the cross-sectional area of fast-twitch skeletal muscle is reduced in HIV-1 Tg rats and mice (35,41). Our data confirm the generalized atrophic response in fast-and slow-twitch muscle in HIV-1 Tg rats and extend this pathological alteration to cardiac muscle.…”

Section: Discussionsupporting

confidence: 76%

“…Consistent with this observation is the increased urinary excretion of 3-MH, as well as the elevated plasma concentrations of all branched-chain amino acids (leucine, isoleucine, and valine) detected in our HIV-1 Tg rats compared with ad libitum-or pair-fed controls. Finally, the increased mRNA content of the E3 ubiquitin ligase atrogin-1 in skeletal muscle observed by us and others (35) is suggestive of enhanced proteolysis. Although many atrophic conditions concomitantly increase atrogin-1 and MuRF1 (3), the increase in the former "atrogene" appears relatively specific in skeletal muscle from HIV-1 Tg rats.…”

Section: Discussionmentioning

confidence: 93%

“…A reduction in gastrocnemius, soleus, and plantaris muscle mass of HIV-1 Tg rats has been reported (35) and differs from the preferential reduction in fast-twitch muscles produced by other catabolic stimuli, including bacterial infection and acute alcohol intoxication (27,50). Moreover, the cross-sectional area of fast-twitch skeletal muscle is reduced in HIV-1 Tg rats and mice (35,41).…”

Section: Discussionmentioning

confidence: 94%

“…Although these types of small animal models are not without their own limitations (48), they offer the opportunity to define the etiology of muscle wasting under well-controlled nutritional and therapeutic conditions and, potentially, to optimize interventions designed to limit the loss of LBM. In this regard, the HIV-1 Tg mouse and rat have a smaller body size than wild-type (WT) littermates, and both have been reported to have a decrease in cross-sectional area in fast-twitch skeletal muscle (35,41). However, neither study controlled the nutritional state of the WT animals (e.g., WT animals were not pair-fed), and neither study systematically investigated possible cellular or physiological mechanisms for the decreased muscle mass.…”

mentioning

confidence: 99%

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Skeletal and cardiac myopathy in HIV-1 transgenic rats

Pruznak

Hong-Brown²,

Lantry

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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The mechanism by which human immunodeficiency virus (HIV)-1 infection in humans leads to the erosion of lean body mass is poorly defined. Therefore, the purpose of the present study was to determine whether transgenic (Tg) rats that constitutively overexpress HIV-1 viral proteins exhibit muscle wasting and to elucidate putative mechanisms. Over 7 mo, Tg rats gained less body weight than pair-fed controls exclusively as a result of a proportional reduction in lean, not fat, mass. Fast- and slow-twitch muscle atrophy in Tg rats did not result from a reduction in the in vivo-determined rate of protein synthesis. In contrast, urinary excretion of 3-methylhistidine, as well as the content of atrogin-1 and the 14-kDa actin fragment, was elevated in gastrocnemius of Tg rats, suggesting increased muscle proteolysis. Similarly, Tg rats had reduced cardiac mass, which was independent of a change in protein synthesis. This decreased cardiac mass was associated with a reduction in stroke volume, but cardiac output was maintained by a compensatory increase in heart rate. The HIV-induced muscle atrophy was associated with increased whole body energy expenditure, which was not due to an elevated body temperature or secondary bacterial infection. Furthermore, the atrophic response could not be attributed to the development of insulin resistance, decreased levels of circulating amino acids, or increased tissue cytokines. However, skeletal muscle and, to a lesser extent, circulating insulin-like growth factor I was reduced in Tg rats. Although hepatic injury was implicated by increased plasma levels of aspartate and alanine aminotransferases, hepatic protein synthesis was not different between control and Tg rats. Hence, HIV-1 Tg rats develop atrophy of cardiac and skeletal muscle, the latter of which results primarily from an increased protein degradation and may be related to the marked reduction in muscle insulin-like growth factor I.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

See 3 more Smart Citations

Skeletal and cardiac myopathy in HIV-1 transgenic rats

Pruznak

Hong-Brown²,

Lantry

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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SIRT1 longevity factor suppresses NF‐κB ‐driven immune responses: regulation of aging via NF‐κB acetylation?

2008

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The aging process involves changes in immune regulation, i.e. adaptive immunity declines whereas innate immunity becomes activated. NF-kappaB signaling is the master regulator of the both immune systems. Two recent articles highlight the role of the NF-kappaB system in aging and immune responses. Adler et al showed that the NF-kappaB binding domain is the genetic regulatory motif which is most strongly associated with the aging process. Kwon et al studying HIV-1 infection and subsequent immune deficiency process demonstrated that HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NF-kappaB complex. As a consequence, the transactivation efficiency of the NF-kappaB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. These observations support the scenario where immune responses and aging process can be enforced by the potentiation of NF-kappaB transactivation efficiency. Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NF-kappaB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.

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The Generation, Detection, and Effects of Reactive Drug Metabolites

et al. 2012

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The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein-reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug-drug interactions that may ensue. One important class of protein-reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates.

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Effect of HIV-1-related protein expression on cardiac and skeletal muscles from transgenic rats

Cited by 44 publications

References 30 publications

Skeletal and cardiac myopathy in HIV-1 transgenic rats

Skeletal and cardiac myopathy in HIV-1 transgenic rats

SIRT1 longevity factor suppresses NF‐κB ‐driven immune responses: regulation of aging via NF‐κB acetylation?

The Generation, Detection, and Effects of Reactive Drug Metabolites

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