Skeletal and cardiac myopathy in HIV-1 transgenic rats

Abstract

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.

Castration differentially alters basal and leucine-stimulated tissue protein synthesis in skeletal muscle and adipose tissue

“…This time course is comparable with other rodent studies where an atrophic response to castration has been demonstrated (10). Body composition, i.e., body fat and LBM, was measured using 1 H nuclear magnetic resonance (NMR) (LF90 Minispec; Bruker, The Woodlands, TX) (46). An oral glucose tolerance test (OGTT) was performed at the end of the 7th week on overnight-fasted rats.…”

“…At the start of the final week of the study, rats were housed individually in metabolic cages and acclimated for 24 h. During the subsequent 24-h period, urine was collected and an aliquot used for HPLC determination of 3-methylhistidine (3-MH) and data normalized to the urinary creatinine concentration (46). 3-methylhistidine is formed by posttranslation modification of histidine released from actin and myosin and provides an in vivo estimate of myofibrillar protein breakdown (42).…”

“…Saline was administered to time-matched control rats, because previous studies indicated that isonitrogenous administration of nonbranched chain amino acids (e.g., alanine) failed to stimulate either protein synthesis or peptide-chain initiation (2). Thereafter, rats were lightly anesthetized by the intraperitoneal injection of the combination of ketamine (40 mg/kg) and acepromazine (1 mg/kg) and M-mode echocardiography performed (Sequoia C256; Siemens Medical Solutions, Mountain View, CA), equipped with a 7.5-MHz transducer (46). All data were collected and analyzed by a single investigator in a blinded manner.…”

Chronic alcohol consumption disrupts myocardial protein balance and function in aged, but not adult, female F344 rats

“…Heart function was assessed by echocardiography using the Sequoia C256 Echocardiography System (Siemens Medical Solutions, Mountain View, CA) equipped with a 7.5-MHz transducer, as described (62). Rats were lightly anesthetized by the intraperitoneal injection of the combination of ketamine (40 mg/kg) and xylazine (1 mg/kg), and body temperature was maintained by heating pad.…”

The role and regulation of MAFbx/atrogin-1 and MuRF1 in skeletal muscle atrophy

“…Using a non-replicative, non-infectious HIV-1 transgenic rat model, chronic expression of HIV-1-related proteins causes atrophy in gastrocnemius, plantaris and soleus muscles with a concomitant increase in MAFbx, but not in MuRF1, mRNA [82,89]. A common treatment for HIV involves the use of various HIV protease inhibitors such as indinavir.…”