Moderate-Intensity Endurance Training Improves Skeletal Microvasculature in Patients with Sickle Cell Disease

An endurance exercise training program of moderate intensity may reverse some of the microvascular deficits of skeletal microvasculature in patients with sickle cell disease (SCD), according to a report published in Blood.

The “profound” muscle microvascular remodeling in patients with SCD may contribute to reduced oxygen delivery to tissues, the authors, led by Angèle Merlet, PhD, from the Laboratoire Interuniversitaire de Biologie de la Motricité in France, explained. “Endurance exercise training is an effective way to improve muscle oxygen supply by increasing capillary density (CD) and tortuosity,” they wrote. “We hypothesized that the proposed moderate-intensity endurance exercise training program would lead to a growth of the capillary network in skeletal muscle in SCD patients.”

In the study, researchers randomized 40 adults with homozygous SCD without severe chronic complications to one of two intervention groups:

  • training: 8-week supervised endurance exercising training program (n=20)
  • non-training: usual lifestyle (n=20)

In the training group, patients followed a personalized moderate-intensity exercise regimen consisting of three 40-minute sessions per week on a cycle ergometer for eight weeks.

To measure changes in microvasculature, researchers performed a biopsy of participants’ vastus lateralis muscle before and after the training period to analyze muscle fiber types and perimeter. Participants also underwent a submaximal incremental ergometer cycling test, which assessed oxygen uptake, tissue saturation index, white blood lactate concentration, and patient-reported perceived exertion (RPE).

A total of 15 patients in the training group and 17 patients in the non-training group completed the study. Baseline characteristics were similar between both groups. Mean ages were 33.6 and 34 (ranges not provided) in the training and non-training groups, respectively, and there were no significant between-group differences in hematologic data or muscle microvasculature – even among patients who were receiving hydroxyurea treatment.

Compared with the non-training group, participants in the training group experienced significant increases in CD, or the number of capillaries per square millimeter (+17%; p=0.003) and the number of capillaries in contact with a single muscle fiber (capillaries around fiber, or CAF; +18%; p=0.015).

The greatest increase in CAF between the training and non-training groups was seen in type I muscle fibers (+23%; p=0.0004), relative to other fiber types. “This fiber-type specific response can be explained by the preferential recruitment of this type of fiber during moderate-intensity endurance exercise training,” the authors wrote.

In all fibers, there was a significant increase of functional exchange surface in patients in the training group, compared with those in the non-training group (+42%; p<0.0001), indicating “an increased surface area between capillaries and muscle fibers, and a decreased diffusion distance,” the authors explained. Both of these factors “are very beneficial for oxygen distribution to muscle tissue of patients with SCD.”

Although the exercise program effectively grew participants’ capillary networks and increased the supply potential of blood and oxygen to muscle tissue, it did not induce changes in the morphology of capillaries. “This lack of change is in accordance with the known low potential for endurance training to alter capillary perimeter and surface area,” the authors wrote.

The observed morphologic changes coincided with improvements of physical activity, determined by patients’ performance on cycle ergometer tests, the investigators reported. Patients who completed the eight-week training program had increased power output and oxygen consumption (+44.6% and +24.7%, respectively; p<0.001).

The investigators concluded that the study provides greater insight into the effects of endurance exercise on microvasculature in those with SCD. “[Our] study suggests that training-induced rearrangement of the microvascular network due to capillary growth may contribute to the concomitant improvement in the patients’ physical capacity,” they wrote. However, they noted several potential limitations of this analysis, including its small sample size and the relatively short duration of the exercise program. The authors added that further research may also be necessary to identify the impact of hydroxyurea and sex on training-induced muscle adaptations in patients with SCD.

The authors report no relevant conflicts of interest.

Reference

Merlet A, Messonnier L, Coudy-Gandilhon C, et al. Beneficial effects of endurance exercise training on skeletal muscle microvasculature in sickle cell disease patients. Blood. 2019.

Compared with the general population, those with SCD expend less energy from physical activity, and the known complications accompanying intense physical activity often act as a deterrent for patients. Skeletal muscle dysfunction impairs their quality of life, but moderate-intensity endurance training may help enhance muscle function and quality of life, a point that has been demonstrated in this study. The effect is due to an increase in capillary density and capillaries around fibers, which lead to an increase in the functional surface of exchange between capillaries and muscle fibers. Also, that patients had an increase in oxygen uptake, with a decrease in lactate and the rate of perceived exertion, proves that growth of the skeletal muscle microvasculature network positively affects clinical outcomes.

As the authors noted, it would be helpful to have data on the effect of hydroxyurea use and gender on exercise-induced alteration in muscle microvasculature and the impact on long-term outcomes using a larger cohort with longer-term endurance training.

In addition, I believe that we would benefit from cautious study of the role of such an intervention in SCD patients with complications. To improve long-term compliance, we should study the role of a step down to a lower-intensity maintenance exercise program after an initial period of moderate-intensity training.

Philip Kuriakose, MD
Henry Ford Hemophilia Treatment Center
Detroit, MI

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