Linking Elastin in Skeletal Muscle Extracellular Matrix to Metabolic and Aerobic Function in Type 2 Diabetes: A Secondary Analysis of a Lower Leg Training Intervention

<b>Background:</b> Type 2 diabetes (T2D) is associated with reduced cardiorespiratory fitness (CRF), a critical predictor of cardiovascular disease and all-cause mortality. CRF relies upon the coordinated action of multiple systems including the skeletal muscle where the mitochondria metabolize oxygen and substrates to sustain ATP production. Yet, previous studies have shown that impairments in muscle bioenergetics in T2D are not solely due to mitochondrial deficits. This finding indicates that factors outside the mitochondria, particularly within the local tissue microenvironment, may contribute to reduced CRF. One such factor is the extracellular matrix (ECM), which plays structural and regulatory roles in metabolic processes. Despite its potential regulatory role, the contribution of ECM remodeling to metabolic impairment in T2D remains poorly understood. We hypothesize that pathological remodeling of the skeletal muscle ECM in overweight individuals with and without T2D impairs bioenergetics and insulin sensitivity, and that exercise may help to ameliorate these effects. <b>Methods:</b> Participants with T2D (<i>n</i> = 21) and overweight controls (<i>n</i> = 24) completed a 10-day single-leg exercise training (SLET) intervention. Muscle samples obtained before and after the intervention were analyzed for ECM components, including collagen, elastin, hyaluronic acid, dystrophin, and proteoglycans, using second harmonic generation imaging and immunohistochemistry. <b>Results:</b> Positive correlations were observed with elastin content and both glucose infusion rate (<i>p</i> = 0.0010) and CRF (0.0363). The collagen area was elevated in participants with T2D at baseline (<i>p</i> = 0.0443) and showed a trend toward reduction following a 10-day SLET (<i>p</i> = 0.0867). Collagen mass remained unchanged, suggesting differences in density. Dystrophin levels were increased with SLET (<i>p</i> = 0.0256). <b>Conclusions:</b> These findings identify that structural proteins contribute to aerobic capacity and identify elastin as an ECM component linked to insulin sensitivity and CRF.