Utility of local capillary supply indices: Insights from computational image-based modelling

Muscle oxygenation critically depends on capillary number and distribution within a tissue. Despite the development of numerous morphometric indices to quantify these attributes, many lack sensitivity or validation against local oxygen tension (PO2 ) in muscle fibres, leading to uncertainty about their physiological relevance and utility for gauging adaptive changes. We assessed six local supply indices to determine which best correlated with and predicted calculated fibre PO2 , using high-throughput histological analysis and image-based computational modelling of oxygen transport on digitised rat tibialis anterior sections: capillary contacts (CCi), individual capillary-to-fibre ratio (C:Fi), capillary-to-fibre perimeter exchange (CFPEi), local capillary-to-fibre ratio (LCFRi), local capillary density (LCDi) and a novel index, Dmax,i, which averages the maximum diffusion distances from capillary domains that overlap a fibre. LCDi and Dmax,i exhibited the strongest correlations with fibre PO2 (linear correlation: 0.8874 and −0.9054, respectively; P < 0.0001). Distance-correlation analysis confirmed both indices as robust predictors of fibre oxygenation (distance correlation: 0.85 and 0.79, respectively; P < 0.0001), demonstrating their ability to capture a curvilinear relationship that plateaus as mean fibre PO2 approaches the capillary source PO2 (P < 0.0001). Partial least squares and tree-ensemble regressions further identified both indices as the most sensitive and critical predictors of fibre PO2 (P < 0.001), suggesting they are less likely to miss early pathophysiological or adaptive responses. These findings support the use of theoretically validated morphometric indices in research and clinical applications, to enhance understanding of fundamental muscle physiology and improve the diagnosis and treatment of muscle-related pathology.