SUMMARY

• 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.

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• To investigate the role of the muscle microcirculation in this anomalous circulatory response and possible implications for the regulation of muscle angiogenesis,

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• 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)

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• despite the fact that oxygen utilization during peak cycle exercise

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• was half that of control subjects (11.1 ± 4.0 ml/kg/min compared with 20.7 ± 7.9 ml/kg/min,

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• 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;

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• and that vascular endothelial growth factor expression paralleled capillary distribution.

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• The increased muscle capillary levels in patients correlated directly (r² = 0.68, P < 0.05) with the severity of the mismatch between systemic oxygen delivery (cardiac output) and oxygen utilization during cycle exercise.

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• Our results suggest that capillary growth is increased as a result of impaired muscle oxidative phosphorylation in mitochondrial myopathy,

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• thus promoting increased blood flow to respiration-incompetent muscle fibres and a mismatch between oxygen delivery and utilization during exercise.

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• 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.

Key words

• mitochondrial DNA defects
• skeletal muscle
• angiogenesis
• regulation of oxygen delivery
• oxidative metabolism

Brain (2012) 135 (1): 53-61. doi: 10.1093/brain/awr293

1. Tanja Taivassalo¹,²,
2. Karen Ayyad²,⁴ and
3. Ronald G. Haller²,³,⁴

+ Author Affiliations

1. 1 Department of Kinesiology, McGill University, Montreal, QC H2W1S4, Canada
2. 2 Neuromuscular Center, Institute for Exercise and Environmental Medicine of Texas Health Presbyterian Hospital, Dallas, TX 75231, USA
3. 3 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390 USA
4. 4 Neurology Division, North Texas VA Medical Centre, Dallas, TX 75216 USA

Correspondence to: Ronald G. Haller, Neuromuscular Center, Institute of Exercise and Environmental Medicine of Texas Health Presbyterian Hospital, 7232 Greenville Ave, Dallas, TX 75231, USA E-mail: Ronald.Haller@UTSouthwestern.edu