Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

References

  1. Bahi L, Koulmann N, Sanchez H, Momken I, Veksler V, Bigard AX et al (2004) Does ACE inhibition enhance endurance performance and muscle energy metabolism in rats? J Appl Physiol 96:59–64

  2. Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F (2007) Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293:H1351–H1358

  3. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M et al (2004) Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPAR gamma-modulating activity. Hypertension 43:993–1002

  4. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

  5. Carter CS, Sonntag WE, Onder G, Pahor M (2002) Physical performance and longevity in aged rats. J Gerontol A Biol Sci Med Sci 57:B193–B197

  6. Carter CS, Cesari M, Ambrosius WT, Hu N, Diz D, Oden S et al (2004) Angiotensin-converting enzyme inhibition, body composition, and physical performance in aged rats. J Gerontol A Biol Sci Med Sci 59:416–423

  7. Carter CS, Onder G, Kritchevsky SB, Pahor M (2005) Angiotensin-converting enzyme inhibition intervention in elderly persons: effects on body composition and physical performance. J Gerontol A Biol Sci Med Sci 60:437–1446

  8. Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219

  9. de Cavanagh EM, Inserra F, Ferder M, Ferder L (2007) From mitochondria to disease: role of the renin–angiotensin system. Am J Nephrol 27:545–553

  10. de Grey AD (2007) The case for prioritizing research on late-onset life-extension interventions in mammals. Rejuvenation Res 10:257–259

  11. Feng X, Luo Z, Ma L, Ma S, Yang D, Zhao Z et al (2010) Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR delta/AMPK pathway. J Cell Mol Med (in press)

  12. Foianini KR, Steen MS, Kinnick TR, Schmit MB, Youngblood EB, Henriksen EJ (2000) Effects of exercise training and ACE inhibition on insulin action in rat skeletal muscle. J Appl Physiol 89:687–694

  13. Gabriely I, Barzilai N (2003) Surgical removal of visceral adipose tissue: effects on insulin action. Curr Diab Rep 3:201–206

  14. Gayagay G, Yu B, Hambly B, Boston T, Hahn A, Celermajer DS et al (1998) Elite endurance athletes and the ACE I allele—the role of genes in athletic performance. Hum Genet 103:48–50

  15. Goodpaster BH, Carlson CL, Visser M, Kelley DE, Scherzinger A, Harris TB et al (2001) Attenuation of skeletal muscle and strength in the elderly: the health ABC Study. J Appl Physiol 90:2157–2165

  16. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV et al (2006) The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 61:1059–1064

  17. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG et al (1994) A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol 49:M85–M94

  18. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K et al (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–395

  19. He H, Yang D, Ma L, Luo Z, Ma S, Feng X et al (2010) Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways. Hypertension 55:869–879

  20. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

  21. Henriksen EJ, Jacob S (2003) Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition. J Cell Physiol 196:171–179

  22. Horiuchi M, Hayashida W, Kambe T, Yamada T, Dzau VJ (1997) Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. J Biol Chem 272:19022–19026

  23. Ikeno Y, Bronson RT, Hubbard GB, Lee S, Bartke A (2003) Delayed occurrence of fatal neoplastic diseases in Ames dwarf mice: correlation to extended longevity. J Gerontol A Biol Sci Med Sci 58:291–296

  24. Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, Seo EJ, Yu BP (1988) The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol 43:B5–B12

  25. Jeong SY, Seol DW (2008) The role of mitochondria in apoptosis. BMB Rep 41:11–22

  26. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

  27. Maeda H, Gleiser CA, Masoro EJ, Murata I, McMahan CA, Yu BP (1985) Nutritional influences on aging of Fischer 344 rats: II. Pathology. J Gerontol 40:671–688

  28. Marzetti E, Groban L, Wohlgemuth SE, Lees HA, Lin M, Jobe H et al (2008a) Effects of short-term GH supplementation and treadmill exercise training on physical performance and skeletal muscle apoptosis in old rats. Am J Physiol Regul Integr Comp Physiol 294:R558–R567

  29. Marzetti E, Wohlgemuth SE, Lees HA, Chung HY, Giovannini S, Leeuwenburgh C (2008b) Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle. Mech Ageing Dev 129:542–549

  30. Marzetti E, Carter CS, Wohlgemuth SE, Lees HA, Giovannini S, Anderson B et al (2009a) Changes in IL-15 expression and death-receptor apoptotic signaling in rat gastrocnemius muscle with aging and life-long calorie restriction. Mech Ageing Dev 130:272–280

  31. Marzetti E, Hwang JC, Lees HA, Wohlgemuth SE, Dupont-Versteegden EE, Carter CS et al (2009b) Mitochondrial death effectors: relevance to sarcopenia and disuse muscle atrophy. Biochim Biophys Acta 1800:235–244

  32. Newman AB, Yanez D, Harris T, Duxbury A, Enright PL, Fried LP (2001) Weight change in old age and its association with mortality. J Am Geriatr Soc 49:1309–1318

  33. Newman AB, Haggerty CL, Goodpaster B, Harris T, Kritchevsky S, Nevitt M et al (2003) Strength and muscle quality in a well-functioning cohort of older adults: the Health, Aging and Body Composition Study. J Am Geriatr Soc 51:323–330

  34. Olshansky SJ, Goldman DP, Zheng Y, Rowe JW (2009) Aging in America in the twenty-first century: demographic forecasts from the MacArthur Foundation Research Network on an Aging Society. Milbank Q 87:842–862

  35. Onder G, Penninx BW, Balkrishnan R, Fried LP, Chaves PH, Williamson J et al (2002) Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: an observational study. Lancet 359:926–930

  36. Rae MJ, Butler RN, Campisi J, de Grey AD, Finch CE, Gough M et al (2010) The demographic and biomedical case for late-life interventions in aging. Sci Transl Med 2:40cm21

  37. Rice KM, Linderman JK, Kinnard RS, Blough ER (2005) The Fischer 344/NNiaHSd X Brown Norway/BiNia is a better model of sarcopenia than the Fischer 344/NNiaHSd: a comparative analysis of muscle mass and contractile properties in aging male rat models. Biogerontology 6:335–343

  38. Santos EL, de Picoli SK, da Silva ED, Batista EC, Martins PJF, D'Almeida V et al (2009) Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats. Biochem Pharmacol 78:951–958

  39. Scarpace PJ, Zhang Y (2009) Leptin resistance: a predisposing factor for diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 296:R493–R500

  40. Schwartz RS (1998) Obesity in the elderly. In: Bray GA, Bouchard C, James WPT (eds) Handbook of obesity. Marcel Dekker, New York, pp 103–114

  41. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC (2010) Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 11:627–636

  42. Song W, Kwak HB, Lawler JM (2006) Exercise training attenuates age-induced changes in apoptotic signaling in rat skeletal muscle. Antioxid Redox Signal 8:517–528

  43. Visser M, Langlois J, Guralnik JM, Cauley JA, Kronmal RA, Robbins J et al (1998) High body fatness, but not low fat-free mass, predicts disability in older men and women: the Cardiovascular Health Study. Am J Clin Nutr 68:584–590

  44. Weisinger RS, Begg DP, Jois M (2009a) Antagonists of the renin–angiotensin system and the prevention of obesity. Curr Opin Investig Drugs 10:1069–1077

  45. Weisinger RS, Stanley TK, Begg DP, Weisinger HS, Spark KJ, Jois M (2009b) Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6 J mice maintained on a high fat diet. Physiol Behav 98:192–197

  46. Yu BP, Masoro EJ, Murata I, Bertrand HA, Lynd FT (1982) Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth, lean body mass and disease. J Gerontol 37:130–141

  47. Zhang Y, Scarpace PJ (2006) The role of leptin in leptin resistance and obesity. Physiol Behav 88:249–256

Download references

Acknowledgments

This study was supported by the National Institute on Aging Grant AG24526, the University of Florida Institute on Aging, The Claude D. Pepper Older Americans Independence Center Grant NIH P30 AG028740, and the McKnight Foundation.

Author information

Correspondence to Christy S. Carter.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s11357-011-9243-3

About this article

Cite this article

Carter, C.S., Giovaninni, S., Seo, D. et al. Differential effects of enalapril and losartan on body composition and indices of muscle quality in aged male Fischer 344 × Brown Norway rats. AGE 33, 167–183 (2011). https://doi.org/10.1007/s11357-010-9196-y

Download citation

Keywords

  • Age-related adiposity
  • Body composition
  • Sarcopenia
  • Renin–angiotensin system
  • Physical function
  • Muscle quality