Pharmacological inhibition of type 5 adenylyl cyclase, a model for healthful aging, enhanced exercise capacity and glucose tolerance

Abstract

Adenylyl cyclase 5 knockout (AC5 KO) is a healthful longevity model; not only do the AC5 KO mice live a third longer than wild-type (WT) mice, but they are also protected against obesity, diabetes, heart failure, and exercise intolerance, mediated by anti-apoptosis, cell survival, myocardial biogenesis, and anti-oxidative stress mechanisms. To translate these salutary effects to the clinics, we developed a drug, C90, which recapitulates the AC5 KO model of healthful longevity. We then examined its effects on glucose tolerance and exercise capacity. C90 (30 mg/kg/day) or vehicle was chronically administered to age-matched C57BL/6 mice via an osmotic pump. The WT mice receiving C90 exhibited improved glucose tolerance, following glucose i.v. injection, when compared to the vehicle. Furthermore, the C90-treated mice had a lower fasting glucose level when compared to the vehicle-treated mice (113 ± 6.5 mg/dL vs. 129 ± 4.2 mg/dL, p ＜ 0.05). Additionally, the WT group that received C90 exhibited greater exercise capacity, reflected by longer running distance (384 ± 27 m vs. 253 ± 16 m, p ＜ 0.05) and greater work to exhaustion (18.1 ± 1.5 J vs. 12.4 ± 0.7 J, p ＜ 0.05) than mice receiving vehicle. In view of these findings, C90 is an excellent candidate for clinical development as an effective pharmacological treatment for glucose intolerance and enhancing exercise performance.

Keywords

adenylyl cyclase 5 / inhibitor / glucose tolerance / exercise / aging

References

[1] Buckenmeyer PJ, Goldfarb AH, Partilla JS, Piñeyro MA, Dax EM. Endurance training, not acute exercise, differentially alters beta-receptors and cyclase in skeletal fiber types. Am J Physiol. 1990; 258: E71-7.

[2] Dohm GL, Pennington SN, Barakat H. Effect of exercise training on adenyl cyclase and phosphodiesterase in skeletal muscle, heart, and liver. Biochem Med. 1976; 16: 138-42.

[3] Esposito G, Perrino C, Ozaki T, Takaoka H, Defer N, Petretta MP, et al. Increased myocardial contractility and enhanced exercise function in transgenic mice overexpressing either adenylyl cyclase 5 or 8. Basic Res Cardiol. 2008; 103: 22-30.

[4] Yan L, Vatner DE, O’Connor JP, Ivessa A, Ge H, Chen W, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007; 130: 247-58.

[5] Ho D, Zhao X, Yan L, Yuan C, Zong H, Vatner DE, et al. Adenylyl Cyclase Type 5 Deficiency Protects Against Diet-Induced Obesity and Insulin Resistance. Diabetes. 2015; 64: 2636-45.

[6] Iwatsubo K, Bravo C, Uechi M, Baljinnyam E, Nakamura T, Umemura M, et al. Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. Am J Physiol Heart Circ Physiol. 2012; 302: H2622-8.

[7] Lai L, Yan L, Gao S, Hu CL, Ge H, Davidow A, et al. Type 5 adenylyl cyclase increases oxidative stress by transcriptional regulation of manganese superoxide dismutase via the SIRT1/FoxO3a pathway. Circulation. 2013; 127: 1692-701.

[8] Okumura S, Takagi G, Kawabe J, Yang G, Lee MC, Hong C, et al. Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload. Proc Natl Acad Sci U S A. 2003; 100: 9986-90.

[9] Vatner DE, Yan L, Lai L, Yuan C, Mouchiroud L, Pachon RE, et al. Type 5 adenylyl cyclase disruption leads to enhanced exercise performance. Aging Cell. 2015; 14: 1075-84.

[10] Zhang J, Levy D, Oydanich M, Bravo CA, Yoon S, Vatner DE, et al. A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion. J Mol Cell Cardiol. 2018; 121: 13-5.

[11] Bravo CA, Vatner DE, Pachon R, Zhang J, Vatner SF. A Food and Drug Administration-Approved Antiviral Agent that Inhibits Adenylyl Cyclase Type 5 Protects the Ischemic Heart Even When Administered after Reperfusion. J Pharmacol Exp Ther. 2016; 357: 331-6.

[12] Levy DE, Abarzúa P, inventors. Adenylyl cyclase inhibitors, pharmaceutical compositions and method of use thereof. United States Patent US10081633B2. 2018 Sep 25.

[13] Oydanich M, Babici D, Zhang J, Rynecki N, Vatner DE, Vatner SF. Mechanisms of sex differences in exercise capacity. Am J Physiol Regul Integr Comp Physiol. 2019; 316: R832-8.

[14] De Lorenzo MS, Chen W, Baljinnyam E, Carlini MJ, La Perle K, Bishop SP, et al. ‘Reduced malignancy as a mechanism for longevity in mice with adenylyl cyclase type 5 disruption’. Aging Cell. 2014; 13: 102-10.

[15] Guers JJ, Zhang J, Campbell SC, Oydanich M, Vatner DE, Vatner SF. Disruption of adenylyl cyclase type 5 mimics exercise training. Basic Res Cardiol. 2017; 112: 59.

[16] Kokkinos P. Physical activity, health benefits, and mortality risk. ISRN Cardiol. 2012; 2012: 718789.

[17] Guo L, Wang C. The effect of exercise on cardiovascular disease risk factors in sedentary population: a systematic review and meta-analysis. Front Public Health. 2025; 13: 1470947.

[18] Schwendinger F, Infanger D, Lichtenstein E, Hinrichs T, Knaier R, Rowlands AV, et al. Intensity or volume: the role of physical activity in longevity. Eur J Prev Cardiol. 2025; 32: 10-9.

[19] Raphael C, Briscoe C, Davies J, Ian Whinnett Z, Manisty C, Sutton R, et al. Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure. Heart. 2007; 93: 476-82.

[20] Mounsey LA, Guo M, Lau ES, Ho JE. Exercise Training in Heart Failure: Clinical Benefits and Mechanisms. Circ Res. 2025; 137: 273-89.

[21] Li H, Liu Y, Liu Y, Xu Z, Pan P, Zeng L. Impact of exercise training on exercise tolerance, cardiac function and quality of life in individuals with heart failure and preserved ejection fraction: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2025; 25: 217.

[22] Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991; 83: 778-86.

[23] Maltese G, McAuley SA, Trawley S, Sinclair AJ. Ageing well with diabetes: the role of technology. Diabetologia. 2024; 67: 2085-102.

[24] Blaha MJ, Hung RK, Dardari Z, Feldman DI, Whelton SP, Nasir K, et al. Age-dependent prognostic value of exercise capacity and derivation of fitness-associated biologic age. Heart. 2016; 102: 431-7.

[25] Regensteiner JG, Sippel J, McFarling ET, Wolfel EE, Hiatt WR. Effects of non-insulin-dependent diabetes on oxygen consumption during treadmill exercise. Med Sci Sports Exerc. 1995; 27: 875-81.

[26] Del Buono MG, Arena R, Borlaug BA, Carbone S, Canada JM, Kirkman DL, et al. Exercise Intolerance in Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019; 73: 2209-25.

[27] American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022; 45: S125-43.

[28] Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al.; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021; 384: 989-1002.

[29] Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016; 375: 311-22.

[30] Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al.; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016; 375: 1834-44.

[31] McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019; 381: 1995-2008.

[32] Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020; 383: 1413-24.

[33] Joseph AM, Adhihetty PJ, Leeuwenburgh C. Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle. J Physiol. 2016; 594: 5105-23.