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    Impaired skeletal muscle fatigue resistance during cardiac hypertrophy is prevented by functional overload- or exercise-induced functional capillarity

    Tickle, PG, Hendrickse, PW, Weightman, A, Nazir, MH, Degens, H ORCID logoORCID: https://orcid.org/0000-0001-7399-4841 and Egginton, S (2021) Impaired skeletal muscle fatigue resistance during cardiac hypertrophy is prevented by functional overload- or exercise-induced functional capillarity. Journal of Physiology, 599 (15). pp. 3715-3733. ISSN 0022-3751

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    Key points: Capillary rarefaction is hypothesized to contribute to impaired exercise tolerance in cardiovascular disease, but it remains a poorly exploited therapeutic target for improving skeletal muscle performance. Using an abdominal aortic coarctation rat model of compensatory cardiac hypertrophy, we determine the efficacy of aerobic exercise for the prevention of, and mechanical overload for, restoration of hindlimb muscle fatigue resistance and microvascular impairment in the early stages of heart disease. Impaired muscle fatigue resistance was found after development of cardiac hypertrophy, but this impairment was prevented by low-intensity aerobic exercise and recovered after mechanical stretch due to muscle overload. Changes in muscle fatigue resistance were closely related to functional (i.e. perfused) microvascular density, independent of arterial blood flow, emphasizing the critical importance of optimal capillary diffusion for skeletal muscle function. Pro-angiogenic therapies are an important tool for improving skeletal muscle function in the incipient stages of heart disease. Abstract: Microvascular rarefaction may contribute to declining skeletal muscle performance in cardiac and vascular diseases. It remains uncertain to what extent microvascular rarefaction occurs in the earliest stages of these conditions, if impaired blood flow is an aggravating factor and whether angiogenesis restores muscle performance. To investigate this, the effects of aerobic exercise (voluntary wheel running) and functional muscle overload on the performance, femoral blood flow (FBF) and microvascular perfusion of the extensor digitorum longus (EDL) were determined in a chronic rat model of compensatory cardiac hypertrophy (CCH, induced by surgically imposed abdominal aortic coarctation). CCH was associated with hypertension (P = 0.001 vs. Control) and increased relative heart mass (P < 0.001). Immediately upon placing the aortic band (i.e. before development of CCH), post-fatigue test FBF was reduced (P < 0.003), coinciding with attenuated fatigue resistance (P = 0.039) indicating an acute arterial perfusion constraint on muscle performance. While FBF was normalized during CCH in chronic groups (P > 0.05) fatigue resistance remained reduced (P = 0.039) and was associated with reduced (P = 0.009) functional capillarity after development of CCH without intervention, indicating a microvascular limitation to muscle performance. Normalization of functional capillarity after aerobic exercise (P = 0.065) and overload (P = 0.329) in CCH coincided with restoration to control levels of muscle fatigue resistance (P > 0.999), although overload-induced EDL hypertrophy (P = 0.027) and wheel-running velocity and duration (both P < 0.05) were attenuated after aortic banding. These data show that reductions in skeletal muscle performance during CCH can be countered by improving functional capillarity, providing a therapeutic target to improve skeletal muscle function in chronic diseases.

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