RESUMEN
A recent seminal paper implicated ischemia-related succinate accumulation followed by succinate-driven reactive oxygen species formation as a key driver of ischemia-reperfusion injury. Although the data show that the mechanism is universal for all organs tested (kidney, liver, heart, and brain), a remaining question is to what extent these observations in mice translate to humans. We showed in this study that succinate accumulation is not a universal event during ischemia and does not occur during renal graft procurement; in fact, tissue succinate content progressively decreased with increasing graft ischemia time (p < 0.007). Contrasting responses were also found with respect to mitochondrial susceptibility toward ischemia and reperfusion, with rodent mitochondria robustly resistant toward warm ischemia but human and pig mitochondria highly susceptible to warm ischemia (p < 0.05). These observations suggest that succinate-driven reactive oxygen formation does not occur in the context of kidney transplantation. Moreover, absent allantoin release from the reperfused grafts suggests minimal oxidative stress during clinical reperfusion.
Asunto(s)
Modelos Animales de Enfermedad , Mitocondrias/metabolismo , Estrés Oxidativo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Ácido Succínico/metabolismo , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Precise determination of the effect of muscle temperature (T(m)) on mitochondrial oxygen consumption kinetics has proven difficult in humans, in part due to the complexities in controlling for T(m)-related variations in blood flow, fiber recruitment, muscle metabolism, and contractile properties. To address this issue, intracellular Po(2) (P(i)(O(2))) was measured continuously by phosphorescence quenching following the onset of contractions in single Xenopus myofibers (n = 24) while controlling extracellular temperature. Fibers were subjected to two identical contraction bouts, in random order, at 15°C (cold, C) and 20°C (normal, N; n = 12), or at N and 25°C (hot, H; n = 12). Contractile properties were determined for every contraction. The time delay of the P(i)(O(2)) response was significantly greater in C (59 ± 35 s) compared with N (35 ± 26 s, P = 0.01) and H (27 ± 14 s, P = 0.01). The time constant for the decline in P(i)(O(2)) was significantly greater in C (89 ± 34 s) compared with N (52 ± 15 s; P < 0.01) and H (37 ± 10 s; P < 0.01). There was a linear relationship between the rate constant for P(i)(O(2)) kinetics and T(m) (r = 0.322, P = 0.03). Estimated ATP turnover was significantly greater in H than in C (P < 0.01), but this increased energy requirement alone with increased T(m) could not account for the differences observed in P(i)(O(2)) kinetics among conditions. These results demonstrate that P(i)(O(2)) kinetics in single contracting myofibers are dependent on T(m), likely caused by temperature-induced differences in metabolic demand and by temperature-dependent processes underlying mitochondrial activation at the start of muscle contractions.
Asunto(s)
Temperatura Corporal , Contracción Muscular/fisiología , Fibras Musculares Esqueléticas/fisiología , Oxígeno/fisiología , Xenopus laevis/fisiología , Adenosina Trifosfato/metabolismo , Animales , Femenino , Mitocondrias Musculares/fisiología , Oxígeno/análisis , Consumo de Oxígeno/fisiologíaRESUMEN
Chronic exposure to hypoxia is associated with muscle atrophy (i.e., a reduction in muscle fiber cross-sectional area), reduced oxidative capacity, and capillary growth. It is controversial whether these changes are muscle and fiber type specific. We hypothesized that different regions of the same muscle would also respond differently to chronic hypoxia. To investigate this, we compared the deep (oxidative) and superficial (glycolytic) region of the plantaris muscle of eight male rats exposed to 4 wk of hypobaric hypoxia (410 mmHg, Po(2): 11.5 kPa) with those of nine normoxic rats. Hematocrit was higher in chronic hypoxic than control rats (59% vs. 50%, P < 0.001). Using histochemistry, we observed 10% fiber atrophy (P < 0.05) in both regions of the muscle but no shift in the fiber type composition and myoglobin concentration of the fibers. In hypoxic rats, succinate dehydrogenase (SDH) activity was elevated in fibers of each type in the superficial region (25%, P < 0.05) but not in the deep region, whereas in the deep region but not the superficial region the number of capillaries supplying a fiber was elevated (14%, P < 0.05). Model calculations showed that the region-specific alterations in fiber size, SDH activity, and capillary supply to a fiber prevented the occurrence of anoxic areas in the deep region but not in the superficial region. Inclusion of reported acclimatization-induced increases in mean capillary oxygen pressure attenuated the development of anoxic tissue areas in the superficial region of the muscle. We conclude that the determinants of tissue oxygenation show region-specific adaptations, resulting in a marked differential effect on tissue Po(2).
Asunto(s)
Hipoxia/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxígeno/fisiología , Animales , Peso Corporal/fisiología , Capilares/fisiología , Tamaño de la Célula , Enfermedad Crónica , Glucólisis/fisiología , Hematócrito , Hemodinámica/fisiología , Cinética , Masculino , Modelos Estadísticos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/citología , Mioglobina/metabolismo , Cadenas Pesadas de Miosina/metabolismo , Miosinas/metabolismo , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/fisiología , Succinato Deshidrogenasa/metabolismoRESUMEN
AIM: To determine whether inhalation of carbon monoxide (CO), resulting in carboxyhaemoglobin (COHb) levels observed in smokers, had an effect on muscle fatigue during electrically evoked and voluntary muscle contractions. METHODS: Young non-smoking males inspired CO from a Douglas bag until their COHb level reached 6%. During the control condition the same participants inspired ambient air from a Douglas bag for 6 min. Fatigue was assessed as the decline in torque in isometric knee extensions, during 2 min of electrically evoked contractions (30 Hz, 1 s on, 1 s off) and during 2 min of maximal isometric voluntary contractions (1 s on, 1 s off). A fatigue index (FI) was calculated as the ratio of final torque : initial torque. Time to peak torque (TPT) and half relaxation time ((1/2)RT) were also determined for the electrically evoked contractions. RESULTS: The FI during both the voluntary fatigue test (control: 0.80 +/- 0.09 vs. CO: 0.70 +/- 0.08; mean +/- SD) and that of the fatigue test with electrically evoked contractions (control: 0.61 +/- 0.09 vs. CO: 0.53 +/- 0.12) was significantly lower after CO inhalation than after inhalation of ambient air (P < 0.05). There was, however, no effect of CO on the changes in TPT or (1/2)RT during the fatigue test. CONCLUSION: Carbon monoxide inhalation resulting in COHb levels found in smokers has an acute impact on the ability of the muscle to resist fatigue.
Asunto(s)
Monóxido de Carbono/administración & dosificación , Fatiga Muscular/fisiología , Músculo Esquelético/fisiología , Esfuerzo Físico/efectos de los fármacos , Administración por Inhalación , Adulto , Carboxihemoglobina/análisis , Electromiografía , Humanos , Exposición por Inhalación , Contracción Isométrica/fisiología , Articulación de la Rodilla/fisiología , Masculino , Esfuerzo Físico/fisiologíaRESUMEN
AIM: To determine whether muscle function is compromised in healthy smokers in comparison with activity-matched non-smokers. METHODS: Nine male smokers (aged 22.2 +/- 2.5 years: mean +/- SD) with a smoking history of 2.5 +/- 3.1 pack years, and ten male control participants (25.4 +/- 2.9 years) matched for physical activity level participated in this study. Knee extensor strength was measured using isometric maximal voluntary contractions. Voluntary activation of the quadriceps and co-activation of the biceps femoris were determined using interpolated twitches and surface electromyography respectively. The frequency-torque relationship and fatigue resistance were assessed with electrically evoked contractions. A fatigue index was determined as the ratio of final torque to initial torque during a series of isometric contractions (2 min; 30 Hz; 1 s contraction/1 s rest). Quadriceps anatomical cross sectional area was measured with MRI at 50% of femur length. RESULTS: Maximal voluntary contraction torque, quadriceps anatomical cross sectional area, knee extensor torque/quadriceps cross sectional area, activation, co-activation and force-frequency relationship were similar, whereas the fatigue index was 17% lower in smokers than non-smokers. CONCLUSION: In young men smoking does not significantly affect quadriceps muscle mass and contractile properties, but does reduce fatigue resistance of the quadriceps muscle, which was not attributable to differences in physical activity.