Distinct structural and functional angiogenic responses are induced by different mechanical stimuli

Kissane, Roger W. P.; Tickle, Peter G.; Doody, Natalie E.; Alshammari, Abdullah; Egginton, Stuart

doi:10.1111/micc.12677

Cited by 7 publications

(10 citation statements)

References 43 publications

(137 reference statements)

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“…This structural profile characterizes phenotypically distinct structural adaptive remodelling, in combination with shifts in metabolism, supporting the differential requirements for oxidative vs. glycolytic metabolism (Annex et al, 1998) (Egginton & Hudlicka, 1999;Scott et al, 1985), where arterial blood flow was unaffected by stimulation, indicating that improvements in EDL function were driven by intrinsic changes within the muscle tissue. Functional improvement in endurance with ES coincided with the increased capillary content/reduced CDA, and consequent reduction in oxygen diffusion distances from capillary to metabolically active fibres predicted to enhance fatigue resistance (Al-Shammari et al, 2014;Kissane et al, 2020;Tickle et al, 2020), providing a clear link between the pacing-derived remodelling of the microcirculation and improved muscle performance.…”

Section: Discussionmentioning

confidence: 82%

Skeletal muscle adaptation to indirect electrical stimulation: divergence between microvascular and metabolic adaptations

Kissane

Hui‐Kang

Tickle

et al. 2023

Experimental Physiology

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New Findings What is the central question of this study?Can we manipulate muscle recruitment to differentially enhance skeletal muscle fatigue resistance? What is the main finding and its importance?Through manipulation of muscle activation patterns, it is possible to promote distinct microvascular growth. Enhancement of fatigue resistance is closely associated with the distribution of the capillaries within the muscle, not necessarily with quantity. Additionally, at the acute stages of remodelling in response to indirect electrical stimulation, the improvement in fatigue resistance appears to be primarily driven by vascular remodelling, with metabolic adaptation of secondary importance. Abstract Exercise involves a complex interaction of factors influencing muscle performance, where variations in recruitment pattern (e.g., endurance vs. resistance training) may differentially modulate the local tissue environment (i.e., oxygenation, blood flow, fuel utilization). These exercise stimuli are potent drivers of vascular and metabolic change. However, their relative contribution to adaptive remodelling of skeletal muscle and subsequent performance is unclear. Using implantable devices, indirect electrical stimulation (ES) of locomotor muscles of rat at different pacing frequencies (4, 10 and 40 Hz) was used to differentially recruit hindlimb blood flow and modulate fuel utilization. After 7 days, ES promoted significant remodelling of microvascular composition, increasing capillary density in the cortex of the tibialis anterior by 73%, 110% and 55% for the 4 Hz, 10 and 40 Hz groups, respectively. Additionally, there was remodelling of the whole muscle metabolome, including significantly elevated amino acid turnover, with muscle kynurenic acid levels doubled by pacing at 10 Hz (P < 0.05). Interestingly, the fatigue index of skeletal muscle was only significantly elevated in 10 Hz (58% increase) and 40 Hz (73% increase) ES groups, apparently linked to improved capillary distribution. These data demonstrate that manipulation of muscle recruitment pattern may be used to differentially expand the capillary network prior to altering the metabolome, emphasising the importance of local capillary supply in promoting exercise tolerance.

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Section: Discussionmentioning

confidence: 82%

Skeletal muscle adaptation to indirect electrical stimulation: divergence between microvascular and metabolic adaptations

Kissane

Hui‐Kang

Tickle

et al. 2023

Experimental Physiology

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“…1995)), potentially incur pharmaceutical side‐effects, may drive angiogenesis without corresponding functional benefit (Kissane et al . 2021), and/or may compound CHF‐derived hypotension via vascular dilatation.…”

Section: Methodsmentioning

confidence: 99%

“…via electrical stimulation or α 1 -blocker administration) were considered less suitable in this context because they either require unwieldy treatment ( e.g. fixing muscle length for long periods by limb imobilisation (Goldspink et al, 1995)), potentially incur pharmaceutical sideeffects, and/or may drive angiogenesis without corresponding functional benefit (Kissane et al, 2021) and may compound CHF-derived hypotension via vascular dilatation.…”

Section: Ii) Aortic Constriction and Edl Overloadmentioning

confidence: 99%

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

Tickle

Hendrickse

Weightman

et al. 2021

The Journal of Physiology

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Capillary rarefaction is hypothesised 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 hind limb 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, emphasising the critical importance of optimal capillary diffusion for skletal muscle function.  Pro-angiogenic therapies are an important tool for improving skeletal muscle function in the incipient stages of heart disease.

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“…These global indices describe gross changes in capillary supply, however, they lack descriptive power of local capillary distribution. The local capillary supply is a critical determinant of functional capacity and of significant importance in the functional overload model which presents with a significant angiogenic response and fibre hypertrophy (Kissane et al, 2020 ; Tickle et al, 2020 ). Therefore, to investigate the influence of concurrent expansion of the capillary bed and fibre hypertrophy on muscle function, we mathematically modelled skeletal muscle oxygen transport kinetics (Al‐Shammari et al, 2019 ).…”

Section: Methodsmentioning

confidence: 99%

C‐bouton components on rat extensor digitorum longus motoneurons are resistant to chronic functional overload

et al. 2021

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Mammalian motor systems adapt to the demands of their environment. For example, muscle fibre types change in response to increased load or endurance demands. However, for adaptations to be effective, motoneurons must adapt such that their properties match those of the innervated muscle fibres. We used a rat model of chronic functional overload to assess adaptations to both motoneuron size and a key modulatory synapse responsible for amplification of motor output, C‐boutons. Overload of extensor digitorum longus (EDL) muscles was induced by removal of their synergists, tibialis anterior muscles. Following 21 days survival, EDL muscles showed an increase in fatigue resistance and a decrease in force output, indicating a shift to a slower phenotype. These changes were reflected by a decrease in motoneuron size. However, C‐bouton complexes remained largely unaffected by overload. The C‐boutons themselves, quantified by expression of vesicular acetylcholine transporter, were similar in size and density in the control and overload conditions. Expression of the post‐synaptic voltage‐gated potassium channel (KV2.1) was also unchanged. Small conductance calcium‐activated potassium channels (SK3) were expressed in most EDL motoneurons, despite this being an almost exclusively fast motor pool. Overload induced a decrease in the proportion of SK3+ cells, however, there was no change in density or size of clusters. We propose that reductions in motoneuron size may promote early recruitment of EDL motoneurons, but that C‐bouton plasticity is not necessary to increase the force output required in response to muscle overload.

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Distinct structural and functional angiogenic responses are induced by different mechanical stimuli

Cited by 7 publications

References 43 publications

Skeletal muscle adaptation to indirect electrical stimulation: divergence between microvascular and metabolic adaptations

Skeletal muscle adaptation to indirect electrical stimulation: divergence between microvascular and metabolic adaptations

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

C‐bouton components on rat extensor digitorum longus motoneurons are resistant to chronic functional overload

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