Introduction
The prevalence of morbidity and mortality for cardiovascular diseases (CVDs) in individuals with a chronic spinal cord injury (SCI) is high relative to ambulatory subjects (Myers et al.
2007). Physical inactivity, which is an independent risk factor of CVD and a central characteristic in individuals having an SCI below the lesion, is likely to accelerate the atherosclerotic process and the consequent increase in cardiovascular risk (Laufs et al.
2005). Interestingly, the increased cardiovascular risk in SCI is unlikely explained by traditional cardiovascular risk factors (i.e. hyperlipidemia and hyperglycemia) (Liang et al.
2007).
A more novel factor is oxidative stress and/or decreased antioxidative capacity in the vascular wall (Yorek
2003). Possibly, an imbalance in (anti)oxidative status may contribute to the increased prevalence of cardiovascular diseases in SCI. The idea of an increased oxidative stress in SCI is further based on the recently described relation between fitness level and oxidative stress in able-bodied subjects (Bloomer and Fisher-Wellman
2008). However, previous studies that examined oxidative stress in individuals with an SCI presented conflicting results, included no other cardiovascular risk factors or lacked the inclusion of able-bodied controls (Kocak et al.
2005; Wozniak et al.
2003). Therefore, the first aim of the present study was to compare baseline levels of oxidative stress and antioxidative capacity from individuals with a chronic SCI with levels in able-bodied subjects. We hypothesized that individuals with an SCI have an increased oxidative stress and a decreased antioxidative capacity compared to able-bodied individuals.
Physical exercise in able-bodied subjects immediately increases levels of oxidative stress (Ji
1999; Powers and Jackson
2008), and subsequently leads to elevated antioxidative enzyme activity (Alessio
1993; Laughlin et al.
1990; Powers and Jackson
2008). Muscle activation by functional electrical stimulation (FES) in individuals with an SCI is demonstrated to immediately increase oxygen consumption and heart rate (Holme et al.
2001), and also represents an efficient manner to alter vascular parameters in the paralyzed limbs in SCI, such as arterial diameter and compliance, blood flow, endothelial function and vascular resistance (de Groot et al.
2005; Hopman et al.
2002; Thijssen et al.
2006). Accordingly, we expected FES exercise to immediately alter oxidative stress, while continuing FES cycling training will improve (anti)oxidative status in SCI. Therefore, the second aim of this study was to assess the acute and long-term effects of electrically induced exercise on oxidative stress and antioxidative capacity in individuals with a chronic SCI.
Discussion
The purpose of this study was to gain more insight into the (anti)oxidative balance under basal conditions and in response to physical exercise in individuals with a chronic SCI as compared to ambulatory subjects. We found that healthy individuals having an SCI without cardiovascular or metabolic disease demonstrate comparable baseline levels of oxidative stress and antioxidative capacity as AB subjects, which suggests that subjects with a chronic SCI demonstrate a preserved (anti)oxidative balance. However, the relation between physical fitness level and oxidative stress in subjects with an SCI indicates that higher fitness levels in subjects with SCI are associated with a better oxidative status. Nonetheless, both a single bout of FES exercise and 8 weeks of FES exercise training had no effect on levels of oxidative stress and antioxidative capacity in subjects having a chronic SCI subjects. These findings suggest that despite the potentially beneficial vascular effects of FES exercise (de Groot et al.
2005; Hopman et al.
2002; Thijssen et al.
2006), training as applied in this study was insufficient to induce changes in the (anti)oxidative balance in subjects with an SCI.
In contrast to our hypothesis, we found preserved baseline levels of MDA, SOD and GPx in individuals with a chronic SCI. A reasonable explanation for this finding may relate to the activity level of our participants. In our study, we included sedentary as well as relatively active subjects with an SCI, who performed up to 6 h of sports a week (e.g. wheelchair basketball, rugby and hand biking). Interestingly, a moderate inverse correlation was found between maximal workload during the maximal hand bike test and baseline levels of oxidative stress. This indicates that a higher aerobic fitness level is associated with a beneficial lower oxidative stress level in subjects with SCI, a finding that was described previously in able-bodied subjects (Bloomer and Fisher-Wellman
2008). This correlation may, at least partly, explain the findings of a previous study which reported a strong correlation between the severity of a cervical lesion and (anti)oxidant status. They reported that a severe spinal cord lesion, which is associated with lower physical activity levels, is related to intensification of oxidative stress and a decrease in antioxidant potential (Wozniak et al.
2003). In line with our hypothesis, oxidative stress levels increase markedly during the first weeks of strict immobilization after the onset of an SCI (Liu et al.
1999). In parallel, also 2–3 months of strict bed rest in healthy subjects causes an increase in oxidative stress, while returning to initial a priori physical activity normalizes (anti)oxidative status (Margaritis et al.
2009). This may also explain why we found a preserved oxidative status in individuals with long-standing SCI, as their activity level in daily living will be increased when compared with strict bed rest.
Despite the moderate correlation between physical activity level and oxidative stress in SCI, levels of MDA, SOD and GPx were unaltered after one bout of FES exercise and 8 weeks of FES exercise training. These findings are in contrast with our hypothesis and several previous studies in rodents (Kanter et al.
1985; Kim et al.
1996; Laughlin et al.
1990), and healthy (Alessio
1993; Evelo et al.
1992; Franzoni et al.
2005; Robertson et al.
1991) and coronary artery diseased humans (Adams et al.
2005; Edwards et al.
2004; Leaf et al.
1999) demonstrating an improvement in (anti)oxidative status after short-term exercise or long-term training. Nonetheless, some studies have also reported unchanged levels of SOD and GPx after intermittent sprint cycle training in healthy subjects (Hellsten et al.
1996), while others found no changes in SOD in trained rats (Alessio and Goldfarb
1988; Laughlin et al.
1990) and in young men after running training (Ohno et al.
1988). It was hypothesized that exercise intensity level is crucial to induce adaptation processes and may explain the conflicting results of previous studies (Goto et al.
2007).
High-intensity exercise (75–100%
VO
2 max) has been shown to result in increased oxidative stress (Goto et al.
2007; Wang et al.
2000) and elevated antioxidative enzyme activities (Powers et al.
1994). Accordingly, high-intensity exercise seems to be most appropriate to alter oxidative status. Based on a previous study, common FES exercise as applied in our study will elevate heart rate to ~123 bpm and increase oxygen uptake up to 63% of the
VO
2 max (Holme et al.
2001). Accordingly, FES cycling exercise in individuals with an SCI does not represent high-intensity exercise and, therefore, may be insufficient to alter (anti)oxidative status. Indeed, even the last FES cycling exercise bout, which was performed at a markedly higher workload and exercise intensity than the first test, did not alter the oxidative stress level in subjects with SCI. A recent study showed that a stronger exercise stimulus can be induced by several technical modifications to the leg cycle ergometer (Janssen and Pringle
2008). One might, therefore, speculate that by extending the duration of the FES exercise training period or by technical modifications, FES exercise would be sufficient to induce changes in (anti)oxidative status. Furthermore, in contrast to FES exercise alone, voluntary arm cranking (alone or combined with FES cycling) may be more suitable to achieve higher exercise intensities. In future studies, measuring MDA levels after the physical fitness test is of additional value to determine if oxidative stress is indeed increased by maximal arm crank exercise.
Another reason that may explain that our findings are related to the muscles of the individuals with SCI. Up-regulation of antioxidative enzymes may be limited to highly oxidative skeletal muscles (Laughlin et al.
1990). Muscles of individuals with SCI show a shift in muscle fiber type towards type IIB (fast twitch, fast fatigable and glycolytic) fibers (Round et al.
1993), which might impair the ability to increase antioxidative enzymes by training in individuals with SCI.
Clinical relevance
Based on the inverse relation between aerobic fitness and level of oxidative stress in SCI individuals, we recommend individuals with a chronic SCI to increase their physical activity level to maintain or even improve their upper-body physical fitness to prevent high levels of oxidative stress. Although a direct relation between oxidative stress levels and cardiovascular risk in individuals with an SCI is unknown, we expect low oxidative stress levels and elevated levels of antioxidative enzymes to reduce cardiovascular risk in SCI.
Limitations
Local measurements of (anti)oxidative status in muscle tissue are preferred over blood analysis, as oxidative stress is primarily induced by the mitochondria. However, indirect (anti)oxidative status assessment from blood samples is commonly accepted and widely applied, while it also has important practical advantages (Edwards et al.
2004; Evelo et al.
1992; Leaf et al.
1999; Ohno et al.
1988). In addition, both SOD and GPx measurements are dependent on specific substrates (selenium and manganese, respectively), which are influenced by dietary intake. Participants registered detailed food intake 3 days prior to baseline measurements, and were asked to keep this similar before the pre- and post-training measurements. This procedure minimized the impact of diet for the comparison between pre- and post-training. We used maximal workload to represent physical fitness in individuals with SCI. This was done because, due to technical problems, we were not able to use oxygen uptake values measured during the physical fitness (arm crank) test. Finally, the relatively small sample size unlikely confounded our results, given the well-controlled, within-subject design and the relatively small variation in the data between- and within subjects.
In conclusion, our results indicate that healthy, non-medicated subjects with a chronic SCI lesion have preserved baseline levels of oxidative stress and antioxidative capacity when compared with able-bodied subjects. However, within the group of subjects with an SCI, a higher aerobic fitness is associated with higher levels of oxidative stress demonstrating the importance to maintain or improve a high physical fitness. Antioxidant capacity is not compromised in moderately active individuals with an SCI. In addition, common FES exercise training does not result in acute or long-term changes in (anti)oxidative status in individuals with an SCI, which is most likely explained by the relatively low-intensity stimulus provided by FES exercise.