Blood Flow and Muscle Fatigue Potential Implications for Cardiovascular Diseases
2614615G
BIOL 3A Human Biology
Dr Katherine Price
University of Glasgow Glasgow, Scotland
October 29, 2022
1. Introduction
1.1 A Potentially Viscous Cycle
Exercise is widely advised to attenuate cardiovascular disease (CVD), yet patients rarely change behaviour after diagnosis (Gerage et al., 2019; Shiba, Shiba and Hatada, 2020). Some of this surely relates to CVD occurring in an already less health-conscious and inactive population, but individuals with CVD may also be less able to engage in physical activity due to greater muscle fatigue (‘peripheral fatigue’) consequent to impaired blood flow, effectively trapping them in a vicious cycle of continued exercise intolerance and worsening CVD. If this is the case, healthcare providers assuming continued lack of physical activity to be solely a matter of patient ‘laziness’ may be missing the chance to meaningfully intervene to counter premature peripheral fatigue secondary to impaired blood flow and limited active hyperaemia.
1.2 Role of Blood Flow in Peripheral Fatigue
Although it was historically believed that blood flow mitigated peripheral fatigue via ATP production and the removal of H+ ions associated with lactic acidosis, pH was not found to be a cause of muscle fatigue (Stackhouse, Reisman and Binder-Macleod, 2001), and moderate activity cannot exhaust ATP (Marieb and Hoehn, 2020, p. 304). This may be why the role of impaired blood flow in CVD exercise intolerance has been overlooked, yet it is not sound to exclude diminished blood flow as a cause of peripheral fatigue altogether First, local ATP debt could still bottleneck Na+/K+–ATPase upregulation in the face of impaired oxygen and glucose delivery (Okamoto et al., 2001, cited in Pirkmajer and Chibalin, 2016) which, combined with inadequate circulation to ‘washout’ metabolites, would leave the K+ effluxed during contraction extracellularly concentrated and Na+ amassed within muscular myocytes The resultant depolarisation would disrupt membrane potential, preventing action potential generation and thus Ca2+ release from the sarcoplasmic reticulum (SR), thereby halting crossbridge formation and preventing contraction, as illustrated in Figure 1.
Figure 1 Sliding Filament Cross-bridge Cycle. Interdictory circle shows the impact of a lack of calcium; without (1) Ca2+ binding to troponin, myosin binding sites will not be exposed, preventing (2) myosin binding to actin to produce force via contraction (‘power stroke’) Adapted from BioRender (2021)
Second, metabolite build-up and the need for greater contractions in still unfatigued fibres to maintain the same overall force result in exercise pressor reflexes - sympathetic stimulation of cardiac output to increase blood flow and meet metabolic demands. The very existence of such a reflex itself suggests that adequate blood flow is paramount to muscular endurance, yet the evidence remains conflicted.
Pitcher and Miles (1997), Broxterman et al (2015), Joyner and Casey (2015), and Weber et al. (2014) all found that reduced blood flow increased fatigability, while Wigmore, Propert and Kent-Braun (2006) observed no relationship between flow and fatigue at all. Hunter (2009) and Samora, Incognito and Vianna (2019) found the role and regulation of blood flow to vary between males and females, suggesting conflicting findings relate to sample variation. Thus, determining if a clear relationship exists between blood flow and muscle fatigue with minimal confounding remains the first step to rule in/out the prospect of a causal role in the low physical activity associated with CVD.
1.3 Hypothesis and Approach
Based on the underlying physiology, it was hypothesised that reduced blood flow markedly hastens peripheral fatigue, but that the time to fatigue varies between males and females To test this without significant confounding from acquired differences in vascular tone or plaque accumulation, a relatively narrow sample was recruited to perform isometric handgrip exercises under occluded and nonoccluded conditions.
2. Methodology
2.1 Sample Demographic
A total of 29 healthy undergraduate students (25 female and four male) from the University of Glasgow were recruited from 2020–2022.
2.2 Experimental Procedures
Subjects were asked to record an initial maximum (100%) handgrip force via transducer before attempting to hold 90%, 75%, 50%, 25%, and 10% (± 5% for each) of that maximum. This was repeated with blood flow occluded using a blood pressure cuff inflated above normal systolic pressure. Subjects were given 2-minute breaks between attempts to minimise longlasting fatigue.
2.3 Data Selection, Exclusions, and Statistical Tests
Durations for 90% and 75% of maximum force were excluded due to reliance on anaerobic fast-twitch type II muscle fibres which are unlikely to be affected by reduced blood flow. 10% durations were further excluded due to being redundant to 25%, as both heavily rely on type I fibres. Data from 10 subjects were further excluded for failure to maintain nonoccluded 50% (±5%) force ≥15 seconds, as this was minimally expected based on the literature, and thus it was likely these subjects misunderstood the instructions (see discussion for further explanation).
The remaining sample was consequently modest in size, but as a t-test is robust against non-normality and significant outliers were excluded, differences in durations, with and without occlusion, were compared via paired t-test. Yet, as normality could not soundly be determined for only three males, and such a miniscule sample would stretch the reliability of any test regardless of robustness, all 19 subjects were analysed and compared to the same data when males were excluded to determine if this could result in different statistical conclusions.
3. Results
Analysing female-only data (n=16) did indeed yield a different conclusion from the analysis of all subjects (n=19) for 50% of maximum force, as reported in Table 1 below.
Table 1. Mean ± SE Handgrip Force Durations, Mean Difference (Δ), and Significance.
∗Conclusion altered by exclusion of male subject data, based on 5% significance (α=0.05)
Presuming female-only data paints an accurate picture (see discussion), there appears to be no significant difference between occluded and nonoccluded durations for 50% handgrip force, but marked differences for 25% force, as illustrated in Figure 2.
Figure 2 Mean ± SE handgrip force durations for female subjects only. Participants fatigued substantially quicker while attempting to hold a grip force of 25% under occluded versus nonoccluded conditions. In contrast, simulated occlusion caused no statistically significant difference in time to fatigue for at 50% of maximum handgrip force
4. Discussion
4.1 Analysis
These findings support reduced blood flow substantially reducing time to fatigue, but only for low-force contractions. It seems possible that 50% of maximum force was not truly impacted, and that initial findings of statistical significance related to either different baseline durations, or different rates of decline, between males and females. Presuming that the declines occur in both, but at different rates and/or from different baselines, the lack of significance may be due greater reliance on anaerobic fast-twitch type II muscle fibre-recruitment at 50% force. Moreover, the intramuscular pressure at 50% may simply be too high for the exercise pressor reflex to properly mitigate metabolite build-up
That the different t-test conclusions were due to differences between males and females is supported by the fact that blood pressure response to physical activity is mediated by changes in cardiac output and total peripheral resistance in males versus only cardiac output in females (Samora, Incognito and Vianna, 2019). Indeed, West et al. (1995) observed women perform isometric handgrip exercises significantly longer than men. It therefore appears that conflicting findings on blood flow and fatigue were due to confounding. Unfortunately, West et al. (1995) only examined seven females, much as this study was limited by observing only three males, making it difficult to draw further conclusions.
4.2
Limitations
The largest limitation of this study relates to the exclusions resulting from confusing instructions in the application subjects used to self-conduct the experiment. In several cases, subjects prematurely terminated attempts once force dropped below 5% of the target level from failure to maintain consistent force, rather than failure to generate force. Further, it is unclear how differences in pain tolerance impacted durations. Finally, all subjects performed nonoccluded contractions prior to occluded, and may have improved in maintaining consistent force over time Yet this supports occlusion shortening time to fatigue, as 25% occluded durations fell despite that ‘practice effect.’
4.3
Conclusion and Future Research
While it is difficult to quantify the degree by which occlusion increases fatigability, it is clear that occlusion does significantly decrease muscular endurance for low-force isometric contractions. This likely explains the lack of behavioural modification in patients with CVD. Future research should further examine differences between males and females, particularly for mild and intermittent occlusion, in addition to exploring potential interventions
References
BioRender (2022). Cross-bridge Cycle. Biorender.com Available at: https://app.biorender.com/ illustrations/6372c6b4ee1e6442d5e52762
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