Background
A spinal cord injury (SCI) is a significant life-changing event which has wide-ranging implications for multiple physiological systems. There are no reliable estimates of the global prevalence of SCI, perhaps reflecting the need for improvements in international medical standards and guidelines for reporting SCI. Over the past 60 years there has been a worldwide improvement in the acute survival of patients with traumatic SCI through the possibility of rapid transportation to a specialised unit, medical treatment advancements and improved rehabilitation [
1]. As a consequence there has been a shift in focus from acute life support medicine, to addressing other secondary health complications and comorbidities associated with ageing with paralysis [
2,
3]. Consequently the long-term demands on medical and support resources are high. A recent systematic review examining survival worldwide after SCI concluded that overall mortality in SCI is up to three times higher than in the general population [
4]. Evidence now suggests that cardiovascular disease (CVD) is the leading cause of mortality in individuals with chronic SCI [
5]. Besides CVD, epidemiological studies have also revealed the incidence of type-2 diabetes mellitus (T2DM) to be high in individuals with SCI [
6‐
8]. Indeed, it has been suggested that adults with SCI are four times more likely to develop T2DM than non-disabled controls [
9].
The contribution of regular physical activity (PA) to reduce the risk of these chronic diseases is well documented and broadly accepted in the non-disabled population [
10,
11]. In individuals with SCI, involvement in sports and recreation is often restricted by the loss of voluntary motor control, as well as autonomic dysfunction and early onset of skeletal muscle fatigue [
12‐
14]. There are also numerous psychosocial and environmental barriers: reduced self-esteem, lack of accessible facilities, unaffordable equipment, fear of injury and/or excessive parental or care protection, which have all been cited as barriers to engagement in PA [
15‐
18]. It is likely that the adoption of a more sedentary lifestyle [
19‐
21], in conjunction with reduced physical function [
22], and adverse changes in body composition [
23,
24] (e.g. lower limb skeletal muscle atrophy [
25,
26]) after SCI, contribute to the increased morbidity and mortality associated with this population.
There is convincing evidence to suggest that component risks for the development of metabolic syndrome occur at a heightened frequency in individuals with SCI; specifically, increased central obesity [
27‐
29], impaired fasting glucose/T2DM [
30,
31] and dyslipidaemia [
32]. The accumulation of excess adiposity is thought to be associated with a sustained positive energy balance secondary to reductions in resting metabolic rate and physical activity energy expenditure. This is associated with local and systemic inflammation, with studies demonstrating a two to threefold increase in the levels of circulating inflammatory markers in persons with SCI compared to non-disabled persons [
33‐
35]. Although elevated chronic inflammation is not formally included among evidence-based metabolic syndrome components, its role in the development of atherosclerosis has been extensively characterised [
36‐
38]. Although it was previously thought that adipose tissue was simply a store for energy, this dynamic tissue is now recognised as an endocrine organ [
39‐
41]. Adipose tissue secretes a number of hormones, collectively termed ‘adipokines’, which play a key role in regulating glucose metabolism and insulin sensitivity, as well as governing aspects of immune function and a variety of other physiological processes. Indeed, the expression of many adipokines is markedly dysregulated with excess adiposity [
42] and in individuals with SCI [
43,
44]. Although a causal link has not been robustly confirmed, several aspects of immune function are also impaired in sedentary, overweight and obese individuals [
45‐
49] and it is possible that these findings may generalise to individuals with SCI [
50].
The impact of physical activity on health in persons with spinal cord injury
Various biological mechanisms, integral in the maintenance of metabolic control, are influenced by physical inactivity and have been implicated in the progression of certain chronic diseases [
51]. To date, cross-sectional evidence has been used to inform PA guidelines for individuals with SCI. These disability-specific guidelines [
52], developed as part of the Study of Health and Activity in People with Spinal Cord Injury (SHAPE SCI) [
53,
54], propose that at least 20 minutes of moderate- to vigorous-intensity aerobic activity should be undertaken twice a week by people with SCI. These guidelines were developed through a systematic and critical appraisal of research to date, which was then deliberated by a multidisciplinary expert panel to assess the quality of the evidence. The comprehensive systematic review to compile this evidence indicated that most studies informing these guidelines were of poor quality and focused solely on physical capacity and muscular strength [
54]. Therefore, there is a lack of empirical evidence regarding the most appropriate dose of exercise or physical activity parameters (e.g. frequency, duration) for improving metabolic health in this population.
The current literature on PA research for individuals with SCI has recently been systematically classified [
55]. Most studies between 2000 and 2012 have been categorised as either: phase 1 (linking PA and health outcomes); phase 2 (validating or developing PA monitors) or; phase 3 (identifying factors influencing behaviour or examining theories of behaviour change). Such categorisation implies that this field is in the early stages of development and research should now focus on phase 4 (evaluating interventions) and phase 5 (disseminating health promotion policies and translating research into practice). Due to the inconsistent findings across studies, concluded via a systematic review requested by the Consortium for Spinal Cord Medicine [
56], it would appear that current evidence is insufficient to determine whether exercise improves carbohydrate and lipid metabolism disorders among adults with SCI. However, previous studies have demonstrated that arm-crank exercise improves lipid profiles [
57], inflammatory biomarkers [
58] and fasting insulin concentrations [
59] with interventions ranging from 12 to 16 weeks in duration. It is possible that inconsistencies in the current literature may be caused by considerable heterogeneity in study participants, the type of exercise programme and/or the outcome measures examined. Here we describe the study design for a randomised controlled trial (RCT) with a homogeneous cohort, examining a variety of outcome measures not simply confined to physical capacity, that will contribute towards our understanding of how a home-based upper body exercise intervention might impact metabolic, cardiovascular and immunological health in individuals with SCI: the HOMEX-SCI study.
Objectives
The primary objective of the HOMEX-SCI study is to assess the impact of a 6-week home-based moderate-intensity arm-crank exercise intervention on markers of metabolic and cardiovascular health in inactive individuals with chronic SCI. Little is known about the impact of a moderate- to vigorous-intensity exercise intervention on messenger ribonucleic acid (mRNA) expression of adipose tissue, which is surprising considering that it is a major site for energy storage. To our knowledge, adipose tissue biology has never been studied in a cohort of individuals with SCI. Thus, a secondary objective is to investigate at baseline, and following intervention, the expression of genes within adipose tissue that are associated with a variety of biological processes such as energy homeostasis, glucose metabolism, lipid metabolism and inflammatory responses. Other objectives include: characterising aspects of adaptive immune function pre and post intervention, quantifying changes in body composition, aerobic capacity, dietary and physical activity behaviours and various constructs of health and wellbeing. The exercise intervention group’s responses, for all outcome measures over 6 weeks, will be compared to a control group.
Discussion
To our knowledge, this will be the first study to simultaneously evaluate the efficacy of a home-based arm-crank ergometry exercise intervention and explore the biological mechanisms of action in persons with chronic SCI. Considering the aforementioned barriers to engage in PA, a convenient and accessible form of exercise is necessary to maximise exercise compliance in this population. A 16-week laboratory-based RCT [
59], which experienced large drop-out rates, has recently advocated that researchers should consider how to make exercise interventions more feasible to individuals with SCI. Home-based arm-crank ergometer exercise has been examined in other hard-to-reach groups (polio patients) [
100] and will overcome transportation barriers and the lack of accessible exercise equipment. Changes in outcome measures with increased PA, achieved through enhanced compliance, may indicate that home-based arm-crank exercise has the potential to be used as a more long-term behavioural strategy to improve clinical outcomes and quality of life in persons with SCI.
Various exercise intervention protocols have been employed for individuals with SCI previously, including arm-crank ergometry [
101], functional electrical stimulation (FES) [
102] or wheelchair propulsion [
103] ranging from between 5 to 57 weeks in duration. The frequency of exercise in these studies was typically between two and three sessions per week lasting 30 to 60 minutes per session. We settled on the proposed intervention of 6 weeks of arm-crank exercise, 4 × 45 minutes per week, in order to provide a considerable exercise stimulus. Over this time-course we expect to see improvements in our primary outcome measure of metabolic control, irrespective of weight loss (which may be negligible as a result of a compensatory increase in energy intake) [
104].
Previous work has demonstrated that genes expressed in skeletal muscle, related to both ‘insulin action’ and ‘adipocytokine signalling’ pathways, are downregulated after 3 weeks of deconditioning in able-bodied males and upregulated after 6 weeks of FES exercise training in individuals with paralysis [
105]. Building on these findings, we speculate that 6 weeks of arm-crank exercise will elicit favourable alterations in the expression of key genes involved in energy homeostasis, glucose metabolism, lipid metabolism and inflammatory pathways in adipose tissue. By examining the expression of genes involved in a variety of biological pathways, we hope to further our understanding of the mechanisms whereby PA might influence metabolic control and inflammation in this population.
It is well established that high levels of habitual PA and/or undertaking structured bouts of exercise can improve aspects of immune function in healthy individuals without a disability [
48,
49,
106,
107]. However, it is unknown whether these findings generalise to people with SCI. Considering that: individuals with SCI exhibit less robust immunity compared to regularly active, lean and able-bodied people [
50]; and that impaired immune function has been reported in sedentary overweight individuals without a disability [
45‐
47], then it is possible that disability-associated impairments in immune function are brought about by sedentary behaviour and adipose tissue accumulation/deregulation. This idea has never been investigated. In the proposed work, we will examine the magnitude of anti-viral cell-mediated immunity (i.e. T cell IFN-γ production) in resting samples pre and post intervention. This response is a functionally relevant and readily observed measure of host immunity that can be assessed sensitively with robust methodology.
The findings from this study might help to inform new evidence-based PA guidelines specific to individuals with a chronic SCI. By taking a holistic approach that addresses a number of relevant outcome measures in a single study, using a rigorous research design (RCT with true control group), this study is in accordance with recent recommendations [
56,
108]. The results will also act as a scientific platform for further interventional studies in other diverse and at-risk populations.
Trial status
Enrolment into the study started on 1 September 2014. As of 2 February 2016, 21/24 participants were recruited. Recruitment is expected to be completed by 29 April 2016 and follow-up assessments in a further 8 weeks.
Abbreviations
ANOVA, analysis of variance; CO2, carbon dioxide; CON, control group; CONSORT, Consolidated Standards of Reporting Trials; CRP, C-reactive protein; CVD, cardiovascular disease; DEXA, Dual-energy X-ray Absorptiometry; EDTA, ethylenediaminetetraacetic acid; ELISA, enzyme-linked immunosorbent assay; ELISpot, enzyme-linked immunospot; EQ-5D-5 L, EuroQol-5 dimensions, 5 levels; ESES, Exercise Self-efficacy Scale; FES, functional electronic stimulation; FSS, Fatigue Severity Scale; HDL-C, high-density lipoprotein cholesterol; HOMA, Homeostasis Model Assessment; iAUC, incremental area under the curve; IFN-γ, interferon gamma; IL-6, interleukin-6; INT, intervention group; LDL-C, low-density lipoprotein cholesterol; METs, metabolic equivalents; NEFA, non-esterified fatty acid; O2, oxygen; OGTT, oral glucose tolerance test; PA, physical activity; PAL, physical activity level; PBMCs, peripheral blood mononuclear cells; RCT, randomised controlled trial; RER, respiratory exchange ratio; RMR, resting metabolic rate; SCI, spinal cord injury; SF-36, short form-36; T2DM, type-2 diabetes mellitus; V̇O2 peak, peak oxygen uptake; WUSPI, Wheelchair User’s Shoulder Pain Index
Acknowledgements
The authors would like to thank the University of Bath for the financial support and Roger and Susan Whorrod for the kind donation to the Centre for DisAbility Sport and Health.