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Influence of aerobic fitness in redox homeostasis: identification and biological implications of cysteine residues oxidation in cardiac and skeletal muscle proteins

Grant number: 14/25957-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2015
Effective date (End): March 31, 2019
Field of knowledge:Biological Sciences - Physiology - Physiology of Effort
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Patricia Chakur Brum
Grantee:Rodrigo Wagner Alves de Souza
Home Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):17/19954-5 - Hemopexin and Heme Oxygenase-1 in Skeletal Muscle: contribution for improving aerobic fitness, BE.EP.PD


Aerobic fitness levels measured as maximal oxygen uptake (VO2 max) is the strongest predictor of morbidity and mortality in both general population and people with chronic diseases. However, the mechanism underlying this strong association is still unresolved. A drawback with clinical studies suggesting a strong statistical association between impaired oxygen metabolism and disease is that VO2 max may be a marker of other behavior not measured, and thus, not adjusted for in the statistical analysis. To further explore whether this association is true, artificial selection for low and high intrinsic running capacity (LCR/HCR rats, respectively) was performed in rats (Koch and Britton 2001) to yield models divergent for diseases risk factors. A series of prospective studies found that metabolic, cardiovascular risk factors, and life span segregate between LCR and HCR rats, which provided the first demonstration that an intrinsic component of oxidative energy metabolism is inherently connected with health and longevity. Loss of capacity for energy dispersal due to impaired aerobic metabolism is a crucial feature underlying the reduced aerobic capacity in LCR. That might rely on an improper redox defense/ oxidative balance further leading to an increased oxidative damage in LCR cardiac and skeletal muscles. In fact, oxidative stress is considered a primary feature underlying disease. Alterations in the cellular redox status or in the levels of reactive oxygen and nitrogen species (ROS and RNS, respectively) are most often sensed by proteins with redox reactive cysteines (Cys) residues, whose thiol oxidative states exert control over the activity of the proteins. Therefore, in the present project, after characterizing the phenotype of LCR and HCR rats, we will use a redox proteomics approach, based on unique properties of Cys side chain that permit a variety of oxidative posttranslational modification (Ox-PTM), to screen distinctly different redox regulated proteins in LCR and HCR cardiac and skeletal muscle (plantaris). We also intend to verify whether the Ox-PTM observed in cardiac and skeletal muscle will be also detectable in serum, conferring a signature of impaired/improved aerobic metabolism in LCR/HCR. We intend to perform target validation through immunoblotting and in vitro functional assays to better molecular mechanisms that link aerobic fitness with health and longevity. (AU)

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Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE SOUZA, RODRIGO W. ALVES; GALLO, DAVID; LEE, GHEE RYE; KATSUYAMA, ERI; SCHAUFLER, ALEXA; WEBER, JANICK; CSIZMADIA, EVA; TSOKOS, GEORGE C.; KOCH, LAUREN G.; BRITTON, STEVEN L.; WISLOFF, ULRIK; BRUM, PATRICIA C.; OTTERBEIN, LEO E. Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity. CELL REPORTS, v. 35, n. 3 APR 20 2021. Web of Science Citations: 0.
VIEIRA, J. S.; CUNHA, T. F.; PAIXAO, N. A.; DOURADO, P. M.; CARRASCOZA, L. S.; BACURAU, A. V. N.; BRUM, P. C. Exercise intolerance establishment in pulmonary hypertension: Preventive effect of aerobic exercise training. Life Sciences, v. 261, NOV 15 2020. Web of Science Citations: 0.
SOUZA, RODRIGO W. A.; ALVES, CHRISTIANO R. R.; MEDEIROS, ALESSANDRA; ROLIM, NATALE; SILVA, GUSTAVO J. J.; MOREIRA, JOSE B. N.; ALVES, MARCIA N.; WOHLWEND, MARTIN; GEBRIEL, MOHAMMED; HAGEN, LARS; SHARMA, ANIMESH; KOCH, LAUREN G.; BRITTON, STEVEN L.; SLUPPHAUG, GEIR; WISLOFF, ULRIK; BRUM, PATRICIA C. Differential regulation of cysteine oxidative post-translational modifications in high and low aerobic capacity. SCIENTIFIC REPORTS, v. 8, DEC 11 2018. Web of Science Citations: 1.
BACURAU, ALINE V. N.; JANNIG, PAULO R.; DE MORAES, WILSON M. A. M.; CUNHA, TELMA F.; MEDEIROS, ALESSANDRA; BARBERI, LAURA; COELHO, MARCELE A.; BACURAU, REURY F. P.; UGRINOWITSCH, CARLOS; MUSARO, ANTONIO; BRUM, PATRICIA C. Akt/mTOR pathway contributes to skeletal muscle anti-atrophic effect of aerobic exercise training in heart failure mice. INTERNATIONAL JOURNAL OF CARDIOLOGY, v. 214, p. 137-147, JUL 1 2016. Web of Science Citations: 9.
BACURAU, ALINE V.; CUNHA, TELMA F.; SOUZA, RODRIGO W.; VOLTARELLI, VANESSA A.; GABRIEL-COSTA, DANIELE; BRUM, PATRICIA C. Aerobic Exercise and Pharmacological Therapies for Skeletal Myopathy in Heart Failure: Similarities and Differences. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2016. Web of Science Citations: 8.

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