TY - JOUR
T1 - Increased capillaries in mitochondrial myopathy
T2 - Implications for the regulation of oxygen delivery
AU - Taivassalo, Tanja
AU - Ayyad, Karen
AU - Haller, Ronald G.
N1 - Funding Information:
The National Institutes of Health [National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS); RO1-AR050597 to R.G.H.]; the Muscular Dystrophy Association USA (to R.G.H. and T.T.); the Natural Sciences and Engineering Council of Canada (NSERC; to T.T.); the Canadian Institutes of Health Research (to T.T.).
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
KW - angiogenesis
KW - mitochondrial DNA defects
KW - oxidative metabolism
KW - regulation of oxygen delivery
KW - skeletal muscle
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U2 - 10.1093/brain/awr293
DO - 10.1093/brain/awr293
M3 - Article
C2 - 22232594
AN - SCOPUS:84856735702
SN - 0006-8950
VL - 135
SP - 53
EP - 61
JO - Brain
JF - Brain
IS - 1
ER -