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

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.

Impaired skeletal muscle performance as a consequence of random functional capillary rarefaction can be restored with overload-dependent angiogenesis.

KEY POINTS: Loss of skeletal muscle capillaries is thought to contribute to a reduction in exercise tolerance, but the relative contribution of a compromised microcirculation with disease, in isolation of co-morbidities, to impaired muscle function is unknown. We therefore developed a novel method to randomly occlude capillaries in the rat hindlimb to mimic the capillary rarefaction observed in many conditions. We demonstrate that muscle fatigue resistance is closely coupled with functional microvascular density, independent of arterial blood flow, while disturbance of the microcirculation leads to long-term impairment of muscle function if left untreated. Mechanical stretch due to muscle overload causes a restoration of fatigue resistance via angiogenic remodelling. These observations highlight the importance of a healthy microcirculation and suggest that restoring impaired microvascular supply, regardless of disease co-morbidities, will assist recovery of exercise tolerance in a variety of conditions that limit quality of life. ABSTRACT: To what extent microvascular rarefaction contributes to impaired skeletal muscle function remains unknown. Our understanding of whether pathological changes in the microcirculation can be reversed remains limited by a lack of basic physiological data in otherwise healthy tissue. The principal objectives here were to: (1) quantify the effect of random microvascular rarefaction on limb perfusion and muscle performance, and (2) determine if these changes could be reversed. We developed a novel protocol in rats whereby microspheres injected into the femoral artery allowed a unilateral reduction in functional capillary density in the extensor digitorum longus (EDL), and assessed acute and chronic effects on muscle function. Simultaneous bilateral EDL force and hindlimb blood flow measurements were made during electrical stimulation. Following functional capillary rarefaction there was an acute microsphere dose-dependent reduction in muscle fatigue resistance (P < 0.001), despite preserved femoral artery perfusion. Histological analysis of EDL samples taken from injected animals confirmed a positive correlation between the proportion of functional capillaries and fatigue resistance (P = 0.002). Such impaired performance persisted for at least 2 weeks (P = 0.016). Concomitant mechanical overload improved both perfused capillary density and fatigue resistance (P<0.05), confirming that the capacity for muscle remodelling was retained following chronic distributed ischaemia, and that the impact of capillary rarefaction could be alleviated. These results demonstrate that loss of functional capillaries is detrimental to muscle function, even in otherwise healthy tissue, independent of arterial perfusion. Restoration of muscle performance following a mechanical overload stimulus indicates that angiogenic treatments to alleviate microvascular rarefaction may be key to restoring exercise tolerance.

Endurance exercise plus overload induces fatigue resistance and similar hypertrophy in mice irrespective of muscle mass.

NEW FINDINGS: What is the central question of this study? Does combining endurance and hypertrophic stimuli blunt the adaptations to both modalities and is this effect greater in muscles with larger baseline fibre cross sectional area? What is the main finding and its importance? Endurance exercise and hypertrophic stimuli can be combined to increase fatigue resistance and fibre size without blunting either adaptation regardless of baseline fibre size. ABSTRACT: Previous studies have demonstrated that fibre cross-sectional area (FCSA) is inversely related to oxidative capacity, which is thought to be determined by diffusion limitations of oxygen, ADP and ATP. Consequently, it is hypothesised that (1) when endurance training is combined with a hypertrophic stimulus the response to each will be blunted, and (2) muscles with a smaller FCSA will show a larger hypertrophic response than those with a large FCSA. To investigate this, we combined overload with endurance exercise in 12-month-old male mice from three different strains with different FCSA: Berlin High (BEH) (large fibres), C57BL/6J (C57) (normal-sized fibres) and Berlin Low (BEL) (small fibres). The right plantaris muscle was subjected to overload through denervation of synergists with the left muscle acting as an internal control. Half the animals trained 30 min per day for 6 weeks. The overload-induced hypertrophy was not blunted by endurance exercise, and the exercise-induced increase in fatigue resistance was not impaired by overload. All strains demonstrated similar absolute increases in FCSA, although the BEH mice with more fibres than the C57 mice demonstrated the largest increase in muscle mass and BEL mice with fewer fibres the smallest increase in muscle mass. This study suggests that endurance exercise and hypertrophic stimuli can be combined without attenuating adaptations to either modality, and that increases in FCSA are independent of baseline fibre size.

The impact of bed rest on human skeletal muscle metabolism.

Insulin sensitivity and metabolic flexibility decrease in response to bed rest, but the temporal and causal adaptations in human skeletal muscle metabolism are not fully defined. Here, we use an integrative approach to assess human skeletal muscle metabolism during bed rest and provide a multi-system analysis of how skeletal muscle and the circulatory system adapt to short- and long-term bed rest (German Clinical Trials: DRKS00015677). We uncover that intracellular glycogen accumulation after short-term bed rest accompanies a rapid reduction in systemic insulin sensitivity and less GLUT4 localization at the muscle cell membrane, preventing further intracellular glycogen deposition after long-term bed rest. We provide evidence of a temporal link between the accumulation of intracellular triglycerides, lipotoxic ceramides, and sphingomyelins and an altered skeletal muscle mitochondrial structure and function after long-term bed rest. An intracellular nutrient overload therefore represents a crucial determinant for rapid skeletal muscle insulin insensitivity and mitochondrial alterations after prolonged bed rest.

Skeletal muscle atrophy, regeneration, and dysfunction in heart failure: Impact of exercise training.

This review highlights some established and some more contemporary mechanisms responsible for heart failure (HF)-induced skeletal muscle wasting and weakness. We first describe the effects of HF on the relationship between protein synthesis and degradation rates, which determine muscle mass, the involvement of the satellite cells for continual muscle regeneration, and changes in myofiber calcium homeostasis linked to contractile dysfunction. We then highlight key mechanistic effects of both aerobic and resistance exercise training on skeletal muscle in HF and outline its application as a beneficial treatment. Overall, HF causes multiple impairments related to autophagy, anabolic-catabolic signaling, satellite cell proliferation, and calcium homeostasis, which together promote fiber atrophy, contractile dysfunction, and impaired regeneration. Although both wasting and weakness are partly rescued by aerobic and resistance exercise training in HF, the effects of satellite cell dynamics remain poorly explored.