Hart, C; (2013) The Effect of Critical Limb Ischaemia on Adult Human Skeletal Muscle. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Potential therapeutic avenues may emerge from understanding morphological adaptations of adult human skeletal muscle that result from critical issue ischaemia (CLI). There is little understanding of the role and limitations of satellite cells in repairing and regenerating ischaemic tissue. This study aims to show the pathognomonic changes that take place as adaptations to chronic ischaemia. Patients (n=10) undergoing lower limb amputations for CLI were recruited to the study and gastrocnemius muscle biopsies were compared to those from control patients (n=10) undergoing long saphenous vein harvesting for coronary artery bypass grafting. Transmission Electron microscopy, histology, immunohistochemistry and Western blotting were used to assess the myogenic response to ischaemia. Any significant change in tissue morphology, morphometry and satellite cell number or activity was of interest. There was significantly greater deposition of fibrofatty tissue, collagen and a loss of polygonal structure in CLI samples. Myonuclear number per fibre was not significantly different, neither was the occurrence of centrally occurring nuclei. All fibre types demonstrated significant atrophy except Ilc. Ilc hybrid fibres were more abundant in CLI samples (p=0.0147). Type I fibres displayed a proportionate rise by 2.4 fold (p=0.0288). Type Ilx fibres were most susceptible to ischaemia with x6 fold reduction in number (p=0.0039) and greatest reduction in CSA (p=0.0029). Type II fibres showed greater fibre-size diversity. The endothelial marker, CD31 and the haematopoietic stem cell marker, CD34 were more abundant in CLI (p<0.0001). There was over expression of the satellite cell marker pax? (p<0.0001) and quiescent satellite cell numbers. MyoD, a marker of activated satellite cells is significantly reduced in ischaemia (p<0.0001). These findings confirm active repair and regeneration in CLI tissue, but the indigenous response of muscle is inadequate for proper healing. These processes are disordered, with limited maturation of myogenesis.

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