Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats

Abstract

The primary purpose of the present set of studies was to provide a direct comparison of the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin receptor blocker losartan on body composition, physical performance, and muscle quality when administered late in life to aged rats. Overall, enalapril treatment consistently attenuated age-related increases in adiposity relative to both placebo and losartan. The maximal effect was achieved after 3 months of treatment (between 24 and 27 months of age), at a dose of 40 mg/kg and was observed in the absence of any changes in physical activity, body temperature, or food intake. In addition, the reduction in fat mass was not due to changes in pathology given that enalapril attenuated age-related increases in tumor development relative to placebo- and losartan-treated animals. Both enalapril and losartan attenuated age-related decreases in grip strength, suggesting that changes in body composition appear dissociated from improvements in physical function and may reflect a differential impact of enalapril and losartan on muscle quality. To link changes in adiposity to improvements in skeletal muscle quality, we performed gene array analyses to generate hypotheses regarding cell signaling pathways altered with enalapril treatment. Based on these results, our primary follow-up pathway was mitochondria-mediated apoptosis of myocytes. Relative to losartan- and placebo-treated rats, only enalapril decreased DNA fragmentation and caspase-dependent apoptotic signaling. These data suggest that attenuation of the severity of skeletal muscle apoptosis promoted by enalapril may represent a distinct mechanism through which this compound improves muscle strength/quality.

Fig. 1

Body weight (upper panel) changes in rats receiving placebo (closed circles), 40 mg/kg enalapril (closed triangles), and 30 mg/kg losartan (open circles) between 24 and 30 months of age. The lower panel depicts changes in rats receiving placebo, 40 mg/kg enalapril, and 30 mg/kg losartan: body weight (left panel), fat mass (middle panel), and lean mass (right panel) between 24 and 27 months of age. All data expressed as means ± SEM

Fig. 2

Forelimb grip strength was measured at baseline and at 27 and 30 months of age in rats receiving placebo (closed circles), 40 mg/kg enalapril (closed triangles), and 30 mg/kg losartan (open circles). All data expressed as means ± SEM

Fig. 3

Changes in food consumption (upper panel; left), locomotor activity (upper panel; right), and body temperature (lower panel) in rats receiving placebo (closed circles), 30 mg/kg losartan (open circles), 40 mg/kg enalapril (closed triangles), and 20 mg/kg enalapril (open triangles) between 24 and 27 months of age. All data expressed as means ± SEM

Fig. 4

Glucose and insulin levels in 27-month-old rats receiving placebo, 40 mg/kg enalapril, 20 mg/kg enalapril and 30 mg/kg losartan between 24 and 27 months of age. All data expressed means ± SEM

Fig. 5

Changes in body weight (upper panel) and fat-to-lean ratio (lower panel) in rats receiving placebo, 40 mg/kg enalapril, and 20 mg/kg enalapril between 24 and 27 months of age. All data expressed as means ± SEM

Fig. 6

Functional network with the highest score of 43 following IPA analysis. Red indicates upregulation; green indicates downregulation. Note that the two central hubs, TP53 and the caspase group, are associated with myonuclear apoptosis

Fig. 7

Changes in apoptotic index as measured by DNA fragmentation in rats receiving placebo), 40 mg/kg enalapril, 20 mg/kg enalapril, and 30 mg/kg losartan between 24 and 27 months of age. All data expressed means ± SEM

Fig. 8

Changes in caspase-dependent apoptotic signaling in rats receiving placebo, 40 mg/kg enalapril, 20 mg/kg enalapril, and 30 mg/kg losartan between 24 and 27 months of age. All data expressed means ± SEM

Fig. 9

Changes in caspase-independent apoptotic signaling in rats receiving placebo, 40 mg/kg enalapril, 20 mg/kg enalapril, and 30 mg/kg losartan between 24 and 27 months of age. All data expressed means ± SEM