Relationship between mitochondrial ROS formation and myofibrillar protein oxidation in contractile dysfunction.

Oxidative stress has been related in numerous cardiovascular and muscular pathologies, but the causal relationship between ROS accumulation and contractile impairment is not clear yet. We hypothesized that upon oxidative stress myofibrillar proteins (MPs) are oxidized providing a relevant contribution to the decrease of contractile performance. The evidence provided in the present work demonstrates the key role of mitochondrial dysfunction in muscle injury. We demonstrated that ROS produced in mitochondria alter MPs causing contractile dysfunction in cardiac and skeletal muscle. These results demonstrated that MP oxidation is an important target of ROS. In addition, this study provides evidence that the MAO-dependent ROS accumulation is responsible for both oxidative modifications of MPs and cell death. In fact, inhibition of MAO protects dystrophic skeletal muscle by reducing ROS production and myofiber degeneration. These results demonstrate the pivotal role of mitochondria and suggest a therapeutic potential for MAO inhibition.Lo stress ossidativo è stato riconosciuto come uno dei meccanismi alla base di molte patologie cardiovascolari e muscolari, ma non è ancora stata chiarita quale possa essere la relazione tra l’elevato accumulo di ROS e la disfunzione contrattile. Noi abbiamo ipotizzato che in presenza di stress ossidativo le proteine miofibrillari (MPs) possano venire ossidate, contribuendo cosi al danno contrattile. I risultati ottenuti in questo lavoro dimostrano che la disfunzione mitocondriale svolge un ruolo chiave nel danno muscolare, sia nelle malattie cardiovascolari che nella distrofia muscolare. Abbiamo dimostrato che le ROS prodotte nel mitocondrio modificano le MPs causando una disfunzione contrattile. Questi risultati dimostrano che le ossidazioni alle MPs sono un importante bersaglio delle ROS. Inoltre questo studio mette in evidenza che le ROS prodotte dalla monoamino ossidasi (MAO) sono responsabili sia delle modifiche a carico delle MPs che della morte cellulare. Infatti l’inibizione farmaceutica della MAO protegge il fenotipo distrofico riducendo la produzione delle ROS e la degenerazione delle fibre muscolari. Questo dimostra il ruolo chiave dei mitocondri nella disfunzione contrattile, suggerendo un nuovo potenziale terapeutico per gli inibitori della MAO

Oxidation of myofibrillar proteins causes contractile dysfunction in human heart failure

Background: Previous studies in microembolized pig hearts (Eur. Heart. J. 27, 875-881, 2006) demonstrated that augmented intracellular accumulation of reactive oxygen species causes oxidative modifications at the level of the contractile machinery. This study was aimed at investigating the role of myofibrillar protein (MP) oxidation\nitrosylation and the relationship between MP oxidation and contractile impairment in human failing myocardium (NYHA class IV). Methods and Results: As compared to samples from non-failing donor hearts (NF-group, n = 15), left ventricular biopsies from explanted failing hearts (NYHA class IV, HF-group, n = 33) displayed a 2.3 \ub1 0.29- and 2.6 \ub1 0.53-fold increase in actin and tropomyosin (Tm) carbonylation respectively, and a 2.2 \ub1 0.47-fold higher level of high-molecular-mass complexes of Tm due to disulphide cross-bridge formation. MP were also modified by reactive nitrogen species. The extent of S-nitrosylation was 1.3 \ub1 0.15-fold higher in the HF-group. Interesting, actin and Tm carbonylation along with Tm oxidation significantly correlated with both loss of viability (r2 = 0.646, P = 6.16E-12; r2 = 0.453, P = 1.58E-07; r2 = 0.221, P = 0.001, respectively), as indicated by plasma TnI levels and contractile impairment (r2 = 0.599, P = 6.88E-112; r2 = 0.457, P = 1.37E-07; r2 = 0.646, P = 6.16E-12, respectively), as shown by reduced left ventricular ejection fraction (LVEF). Conclusion: This study demonstrates that HF-related oxidative and nitrosative stresses induce covalent changes of MP and that these MP changes play a relevant role in contractile impairment as suggested by the inverse correlation between MP oxidation and LVEF

Mitochondrial injury and protection in ischemic pre- and postconditioning

: Mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability, yet a mild degree of mitochondrial dysfunction appears to underlie cardioprotection against injury caused by postischemic reperfusion. This review is focused on two major mechanisms of mitochondrial dysfunction, namely, oxidative stress and opening of the mitochondrial permeability transition pore. The formation of reactive oxygen species in mitochondria will be analyzed with regard to factors controlling mitochondrial permeability transition pore opening. Finally, these mitochondrial processes are analyzed with respect to cardioprotection afforded by ischemic pre- and postconditioning

Alisporivir rescues defective mitochondrial respiration in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe muscle disease of known etiology without effective, or generally applicable therapy. Mitochondria are affected by the disease in animal models but whether mitochondrial dysfunction is part of the pathogenesis in patients remains unclear. We show that primary cultures obtained from muscle biopsies of DMD patients display a decrease of the respiratory reserve, a consequence of inappropriate opening of the permeability transition pore (PTP). Treatment with the cyclophilin inhibitor alisporivir − a cyclosporin A derivative that desensitizes the PTP but does not inhibit calcineurin − largely restored the maximal respiratory capacity without affecting basal oxygen consumption in cells from patients, thus reinstating a normal respiratory reserve. Treatment with alisporivir, but not with cyclosporin A, led to a substantial recovery of respiratory function matching improved muscle ultrastructure and survival of sapje zebrafish, a severe model of DMD where muscle defects are close to those of DMD patients. Alisporivir was generally well tolerated in HCV patients and could be used for the treatment of DMD