María Morán

Mitochondrial respiratory chain dysfunction: implications in neurodegeneration.

For decades mitochondria have been considered static round-shaped organelles in charge of energy production. In contrast, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival, because of their role in the modulation of apoptosis, autophagy, and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions and the implication of mitochondrial dysfunction in multifactorial human pathologies such as cancer, Alzheimer and Parkinson diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields for exploring the roles of these mitochondrial pathways in human pathologies. This review dissects the relationships between activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus on their implications for neurodegeneration.

Favorable responses to acute and chronic exercise in McArdle patients.

Objective:This study reports acute exercise responses in a large (N = 46) series of patients with McArdle disease and responses to exercise training in a smaller (n = 9) set of patients. Design:Patients were studied during both incremental and steady-state cycle ergometer exercise, using cardiopulmonary testing, and the patients were compared with age- and gender-matched controls. Setting:The study was performed in a university setting (clinical exercise physiology laboratory). Participants:The 46 patients showed common features of McArdle disease. They were definitively diagnosed by histochemistry, biochemistry, and/or molecular genetic analysis. The 46 controls were healthy, sedentary individuals. Intervention:Nine patients were studied before and after an 8-month supervised aerobic exercise training program (including five weekly sessions of walking and/or cycling exercise with a duration no greater than 60 minutes). Main Outcome Measurements:The main indicators of exercise capacity that we measured were peak power output, peak oxygen uptake (VO2peak), and ventilatory threshold (VT). Results:Exercise capacity (peak power output, 35% control; VO2peak, 44% control; VT, 66% control) was markedly depressed in the patients. The patients who trained improved peak power output (25%), VO2peak (44%), and VT (27%), with no evidence of negative outcomes from training. Although not achieving normal values, the response to training put the patients into the lower limit of normal controls. Conclusions:Under carefully controlled conditions, patients with McArdle disease may perform acute exercise safely, and they may respond favorably to training. This may offer an additional therapeutic option to help normalize the lifestyles of these patients.

BECOMING A CITIZEN

ABSTRACT Although citizenship and youth have traditionally seemed to be two terms with very little in common, recent years have shown an enormous interest in analysing their relationships. On one hand, exploring how the new generations become citizens is a key issue for understanding the characteristics of the civic life of a society. On the other, the concept of citizenship has revealed itself as a potent conceptual and analytic instrument for explaining youth transitions. In order to acquire a deeper comprehension of these relationships, we believe it necessary to advance in their empirical study, to acknowledge their multidimensional character, and to defend a dynamic perspective of citizenship. This paper approaches the study of citizenship from its cultural dimension and proposes an analytical framework for the empirical study of the discourses and representations of what being a citizen means to young Europeans. Our analytical framework is structured along two axes: the dimension of belonging and the dimension of involvement.

Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency.

Mutations in BCS1L, an assembly factor that facilitates the insertion of the catalytic Rieske Iron‐Sulfur subunit into respiratory chain complex III, result in a wide variety of clinical phenotypes that range from the relatively mild Björnstad syndrome to the severe GRACILE syndrome. To better understand the pathophysiological consequences of such mutations, we studied fibroblasts from six complex III‐deficient patients harboring mutations in the BCS1L gene. Cells from patients with the most severe clinical phenotypes exhibited slow growth rates in glucose medium, variable combined enzyme deficiencies, and assembly defects of respiratory chain complexes I, III, and IV, increased H2O2 levels, unbalanced expression of the cellular antioxidant defenses, and apoptotic cell death. In addition, all patients showed cytosolic accumulation of the BCS1L protein, suggestive of an impaired mitochondrial import, assembly or stability defects of the BCS1L complex, fragmentation of the mitochondrial networks, and decreased MFN2 protein levels. The observed structural alterations were independent of the respiratory chain function and ROS production. Our results provide new insights into the role of pathogenic BCS1L mutations in mitochondrial function and dynamics. Hum Mutat 31:–12, 2010.

Exercise attenuates the major hallmarks of aging.

Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.

Strenuous endurance exercise improves life expectancy: it's in our genes

The effect of strenuous, competitive exercise on the human heart and life expectancy has long been a subject of debate. For centuries, the general belief was that vigorous, competitive exercise was harmful and decreased life expectancy. However, a number of studies of the early 20th century, together with more recent data in elite athletes, strongly support the notion that participation in competitive sports is associated with normal or increased life expectancy, with a special beneficial effect of aerobic type of activities. In terms of genetics, current humans are citizens of the Paleolithic era living in the 21st century, so that those who better match with an active lifestyle will likely have a longer life expectancy and a reduced risk of chronic diseases. Endurance athletes might be such an example. The effect of strenuous, competitive exercise on human life expectancy has long been a subject of debate. Since the classical antiquity, the prevailing belief has been that vigorous, competitive exercise is harmful. Hippocrates wrote about athletes that ‘…the truth is, however, that no one is in a more risky state of health than they….’1 Similar was the opinion of the Greek physician–philosopher Galen. Galens beliefs were that ‘Athletes live a life quite contrary to the precepts of hygiene…when they give up their profession, they fall into a dangerous condition; as a fact, some die shortly afterwards, others live for some little time but do not arrive at old age..’2 The belief that vigorous exercise was harmful remained for centuries. In 1968, Moorstein3 stated that all members of the 1948 Harvard rowing crew had died early from ‘various cardiac diseases.’ A number of studies of the early 20th century and thereafter, however, showed that participation in endurance competitive sports increased life expectancy (table 1). View this table: Table 1 Summary of the main …

Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient

Mutations in BCS1L, a respiratory chain complex III assembly chaperone, constitute a major cause of mitochondrial complex III deficiency and are associated with GRACILE and Björnstad syndromes. Here we describe a 4-year-old infant with hyperlactacidemia, mild liver dysfunction, hypotonia, growth and psychomotor retardation, dysmorphic features and mitochondrial complex III deficiency. Respiratory chain enzyme activities showed an isolated complex III defect in muscle and fibroblasts. Sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed a novel homozygous BCS1L mutation, c.148A>G, which caused a p.T50A substitution at an evolutionarily conserved BCS1L region. The severity of the complex III enzyme defect correlated with decreased amounts of BCS1L and respiratory chain complex III in the affected tissues. Our findings support a pathogenic role for the novel BCS1L mutation in a patient with a singular clinical phenotype.

The K153R Polymorphism in the Myostatin Gene and Muscle Power Phenotypes in Young, Non-Athletic Men

The Lys(K)153Arg(R) polymorphism in exon 2 (rs1805086, 2379 A>G replacement) of the myostatin (MSTN) gene is a candidate to influence skeletal muscle phenotypes. We examined the association between the MSTN K153R polymorphism and ‘explosive’ leg power, assessed during sprint (30 m) and stationary jumping tests [squat (SJ) and counter-movement jumps (CMJ)] in non-athletic young adults (University students) [n = 281 (214 men); age: 21–32 years]. We also genotyped the MSTN exonic variants E164K (rs35781413), I225T, and P198A, yet no subject carried any of these variant MSTN alleles. As for the K153R polymorphism, we found only one woman with the KR genotype; thus, we presented the results only for men. The results of a one-way ANCOVA (with age, weight and height entered as covariates) showed that men with the KR genotype (n = 15) had a worse performance in vertical jumps compared with those with the KK genotype [SJ: vertical displacement of center of gravity (CG) of 35.17±1.42 vs. 39.06±0.39 cm, respectively, P = 0.009; CMJ: vertical displacement of CG of 36.44±1.50 vs. 40.63±0.41 cm, respectively, P = 0.008]. The results persisted after adjusting for multiple comparisons according to Bonferroni. Performance in 30 m sprint tests did however not differ by K153R genotypes. In summary, the MSTN K153R polymorphism is associated with the ability to produce ‘peak’ power during muscle contractions, as assessed with vertical jump tests, in young non-athletic men. Although more research is still needed, this genetic variation is among the numerous candidates to explain, alone or in combination with other polymorphisms, individual variations in muscle phenotypes.

Are 'endurance' alleles 'survival' alleles? Insights from the ACTN3 R577X polymorphism.

Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching ≥100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein α-actinin-3. We compared the ACTN3 R577X genotype/allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n = 64; 57 female; age range: 100–108 years), young healthy controls (n = 283, 67 females, 216 males; 21±2 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P = 0.019) and XX genotype (P = 0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (α-actinin-3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by α-actinin-3 deficiency and the ‘endurance’/oxidative muscle phenotype that is commonly associated with this condition.

Antioxidants and ecto‐5′‐nucleotidase are not involved in the training‐induced cardioprotection against ischaemia–reperfusion injury

Isolated Langendorff‐perfused hearts from sedentary and prolonged (24 weeks) treadmill‐trained rats were subjected to 30 min of normoxic perfusion either alone or followed by 20 min of global ischaemia, or by 20 min of global ischaemia and 15 min of normoxic reperfusion. Pre‐ischaemic values of antioxidant enzyme activities and ecto‐5′‐nucleotidase activity were not different in sedentary and trained hearts but a 5‐fold increase of 72‐kDa heat shock protein (HSP72) levels was detected in trained myocardium. After ischaemia and reperfusion (I/R), metabolic recovery was better in trained than in sedentary hearts as indicated by higher ATP and creatine phosphate levels. However, antioxidant enzymatic activities, glutathione reductase, and total and mitochondrial superoxide dismutase decreased in trained rats after I/R, whereas they remained unchanged in the sedentary ones. Ecto‐5′‐nucleotidase activity was modified by I/R in sedentary as well as in trained hearts while HSP72 content did not change. Ecto‐5′‐nucleotidase activity and HSP72 content increased in parallel by the 30‐min perfusion period. In conclusion, the cardioprotection induced by long‐term training could be mediated by the exercise‐induced increase in HSP72 levels and is not related to enhanced antioxidant systems or ecto‐5′‐NT activity.