Taivassalo T.,McGill University |
Taivassalo T.,The Texas Institute |
Ayyad K.,The Texas Institute |
Ayyad K.,North Texas Medical Center |
And 3 more authors.
Brain | Year: 2012
Human skeletal muscle respiratory chain defects restrict the ability of working muscle to extract oxygen from blood, and result in a hyperkinetic circulation during exercise in which oxygen delivery is excessive relative to oxygen uptake and oxygen levels within contracting muscle are abnormally high. To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis, we assessed muscle oxidative capacity during cycle exercise and determined capillary levels and distribution and vascular endothelial growth factor expression in quadriceps muscle biopsies in patients with mitochondrial myopathy attributable to heteroplasmic mitochondrial DNA mutations. We found that in patients with mitochondrial myopathy, muscle capillary levels were twice that of sedentary healthy subjects (3.0±0.9 compared with 1.4±0.3, P<0.001) despite the fact that oxygen utilization during peak cycle exercise was half that of control subjects (11.1±4.0ml/kg/min compared with 20.7±7.9ml/kg/min, P<0.01); that capillary area was greatest in patients with the most severe muscle oxidative defects and was more than two times higher around muscle fibre segments with defective (i.e. cytochrome oxidase negative/succinic dehydrogenase-positive or 'ragged-red' fibres) compared with more preserved respiratory chain function; and that vascular endothelial growth factor expression paralleled capillary distribution. The increased muscle capillary levels in patients correlated directly (r 2=0.68, P<0.05) with the severity of the mismatch between systemic oxygen delivery (cardiac output) and oxygen utilization during cycle exercise. Our results suggest that capillary growth is increased as a result of impaired muscle oxidative phosphorylation in mitochondrial myopathy, thus promoting increased blood flow to respiration-incompetent muscle fibres and a mismatch between oxygen delivery and utilization during exercise. Furthermore, the finding of high capillary levels despite elevated tissue oxygen levels during exercise in respiration-deficient muscle fibres implies that mitochondrial metabolism activates angiogenesis in skeletal muscle by a mechanism that is independent of hypoxia. © 2011 The Author.
Crooks D.R.,Georgetown University |
Crooks D.R.,U.S. National Institutes of Health |
Jeong S.Y.,U.S. National Institutes of Health |
Tong W.-H.,U.S. National Institutes of Health |
And 6 more authors.
Journal of Biological Chemistry | Year: 2012
Iron-sulfur (Fe-S) cluster cofactors are formed on the scaffold protein ISCU. ISCU myopathy is a disease caused by an intronic mutation that leads to abnormally spliced ISCU mRNA. We found that two predominant mis-spliced ISCU mRNAs produce a truncated and short-lived ISCU protein product in multiple patient cell types. Expression of the muscle-specific transcription factor MyoD further diminished normal splicing of ISCU mRNA in patient myoblasts, demonstrating that the process of muscle differentiation enhances the loss of normal ISCUmRNA splicing. ISCU protein was nearly undetectable in patient skeletal muscle, but was higher in patient myoblasts, fibroblasts, and lymphoblasts.Wenext treated patient cells with pro-oxidants to mimic the oxidative stress associated with muscle activity. Brief hydrogen peroxide treatment or incubation in an enriched oxygen atmosphere led to a marked further reduction of ISCU protein levels, which could be prevented by pretreatment with the antioxidant ascorbate. Thus, we conclude that skeletal muscle differentiation of patient cells causes a higher degree of abnormal ISCU splicing and that oxidative stress resulting from skeletal muscle work destabilizes the small amounts of normal ISCU protein generated in patient skeletal muscles.
Heinicke K.,The Texas Institute |
Heinicke K.,University of Texas Southwestern Medical Center |
Taivassalo T.,McGill University |
Wyrick P.,The Texas Institute |
And 7 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2011
Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low V O 2peak (28 ± 9% of predicted) and exaggerated systemic O 2 delivery relative to O 2 utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/V O 2peak, (MM = 104 ± 18; C = 42 ± 8, P ≤ 0.001), and VE/VCO 2peak, (MM = 54 ± 9; C = 34 ± 7, P ≤ 0.01); a steeper slope of increase in δVE/ΔVCO 2 (MM = 50.0 ± 6.9; C = 32.2 ± 6.6, P ≤ 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 ± 0.31, C = 1.25 ± 0.03, P ≤ 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower PaCO2 and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated V E/V O 2, V E/V CO 2, and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation. © 2011 by the American Physiological Society.
Sharp L.J.,University of Texas Southwestern Medical Center |
Sharp L.J.,The Texas Institute |
Haller R.G.,University of Texas Southwestern Medical Center |
Haller R.G.,The Texas Institute |
Haller R.G.,North Texas Medical Center
Neurologic Clinics | Year: 2014
Metabolic and mitochondrial myopathies encompass a heterogeneous group of disorders that result in impaired energy production in skeletal muscle. Symptoms of premature muscle fatigue, sometimes leading to myalgia, rhabdomyolysis, and myoglobinuria, typically occur with exercise that would normally depend on the defective metabolic pathway. But in another group of these disorders, the dominant muscle symptom is weakness. This article reviews the clinical features, diagnosis, and management of these diseases with emphasis on the recent literature. © 2014 Elsevier Inc.
Camacho C.V.,University of Texas Southwestern Medical Center |
Mukherjee B.,University of Texas Southwestern Medical Center |
McEllin B.,University of Texas Southwestern Medical Center |
Ding L.,University of Texas Southwestern Medical Center |
And 12 more authors.
Carcinogenesis | Year: 2010
DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. We previously demonstrated that complex DSBs induced by high-linear energy transfer (LET) Fe ions are repaired slowly and incompletely, whereas those induced by low-LET gamma rays are repaired efficiently by mammalian cells. To determine whether Fe-induced DSBs are more potently tumorigenic than gamma ray-induced breaks, we irradiated 'sensitized' murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and injected the surviving cells subcutaneously into nude mice. Using this model system, we find that Fe ions are potently tumorigenic, generating tumors with significantly higher frequency and shorter latency compared with tumors generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied by rampant genomic instability and multiple genomic changes, the most interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional loss of p15/Ink4b in tumors derived from cells that are already deficient in p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor suppression, especially in the absence of p16. Indeed, we find that reexpression of p15 in tumor-derived cells significantly attenuates the tumorigenic potential of these cells, indicating that p15 loss may be a critical event in tumorigenesis triggered by complex DSBs. © The Author 2010. Published by Oxford University Press. All rights reserved.