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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Rheumatoid arthritis (RA) is characterized by, and a major cause of disability. Recently, Giles et al (1) showed that disability in patients with RA is linked to adverse changes in body composition, with mean Health Assessment Questionnaire (HAQ) scores being inversely related to appendicular lean mass (ALM; a surrogate measure of skeletal muscle mass), and directly related to appendicular fat mass. Unfortunately, both reduced muscle mass, termed rheumatoid cachexia (2), and increased adiposity are associated with RA (3). In fact, according to the definitions proposed by Baumgartner et al (4), 67% of our whole-body dual x-ray absorptiometry (DXA)–assessed patients with RA are muscle wasted, and 80% are obese (5–7).
Relative to age- and sex-matched healthy sedentary controls, the loss in lean body mass (LBM) that we observe averages ∼15% (Lemmey et al: unpublished observations); a magnitude in accordance with the 14–16% reductions in body cell mass identified by Roubenoff et al for patients with RA (8, 9). This degree and prevalence of rheumatoid cachexia is alarming because, in addition to diminished function and increased disability, muscle loss is associated with impaired immune and pulmonary function, osteoporosis, glucose intolerance, and increased mortality (10). Consequently, interventions that can increase muscle mass in cachectic individuals have the potential to improve physical performance and decrease morbidity and mortality (11).
In a nonrandomized pilot study (5), we showed that 12 weeks of high-intensity progressive resistance training (PRT; 3 days/week) significantly increased LBM and ALM, decreased percent body fat, and substantially improved objective functional capacity in cachectic patients with RA. Similarly, Hakkinen et al (12) subsequently found that combined strength and aerobic training increased thigh muscle mass and decreased thigh fat mass in female patients with RA. However, these body composition results are at odds with the earlier investigation of Rall et al (13), in which PRT failed to augment LBM in patients with RA. Therefore, the efficacy of PRT in restoring muscle mass in patients with RA requires confirmation.
Also awaiting clarification are the mechanisms by which exercise-induced improvements are made, and further insights into the pathology of rheumatoid cachexia are also needed. It is likely that the insulin-like growth factor (IGF) system plays a key role in these processes, because IGF-1 produced locally in the muscle (mIGF-1) is thought to regulate adult skeletal muscle maintenance and its hypertrophic adaptation to increased loading (14). In support of this, significantly reduced mIGF-1 levels have been identified in conditions characterized by muscle wasting (15–18). Furthermore, the success of exercise training in restoring muscle mass in these conditions appears to be dependent on whether mIGF-1 levels respond to the exercise stimulus (15, 18, 19).
Consequently, in the current randomized controlled study we aimed to confirm our preliminary observations (i.e., that PRT reverses debilitating cachexia and improves function in patients with RA), and to investigate the role of the local IGF system in exercise-induced hypertrophy of skeletal muscle in patients with RA.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
In this randomized controlled trial, we have confirmed our pilot study findings (5) that PRT significantly increases muscle mass and restores physical function in patients with RA. In addition, we have identified a probable mechanism for muscle anabolism in RA.
The results of Rall et al (13) suggested that patients with RA, perhaps due to their hypermetabolic state, were resistant to the anabolic effects of exercise. However, subsequent studies (5, 12), and especially the current investigation, which features a more robust methodologic design, refute this. Our pilot study (5) and the current trial have both observed marked increases in LBM, ALM, and total body protein following high-intensity PRT, and Hakkinen et al (12) demonstrated increases in quadriceps femoris thickness (P < 0.001) in female patients with RA following 21 weeks of PRT combined with aerobic training. Similarly, these studies consistently show reductions in fat following training. In the study by Hakkinen et al (12), quadriceps femoris subcutaneous fat thickness decreased (P < 0.001); in our pilot study (4), percent body fat was reduced (P < 0.05) and there was a trend for trunk fat mass to decrease (−752 gm; P = 0.084); and in the current study, physiologically significant reductions in fat mass (2.3 kg) and trunk fat mass (2.5 kg, i.e., 18%) were observed. This repeated suggestion that PRT reduces trunk fat mass is of clinical interest because RA predisposes to central obesity (31) and, consequently, insulin resistance, dyslipidemia, hypertension, and the metabolic syndrome (32).
One difference between the studies that achieved exercise training–induced improvements in body composition in patients with RA (refs.5, 12, and the current study) and that of Rall et al (13), which did not, is volume of training. Whereas in the earlier investigation (13) subjects on average completed only 21 training sessions (2 sessions/week for 12 weeks with 87% compliance), at least 30 sessions were completed, on average, in the other trials. Additionally, the training implemented by Rall and colleagues involved performing only 5 exercises per session (13), whereas our program featured 8 different exercises (ref.5, and the current study).
In terms of the magnitude of training effect, the body composition changes we observed correspond to those typically seen for healthy middle-aged or older subjects following 3–12 months of high-intensity PRT (33, 34). A more direct comparison is provided by Hakkinen et al (12), who found almost identical increases in thigh muscle and comparable reductions in thigh fat in female patients with RA and age-matched, healthy women following completion of the same training program. Therefore, it is now clear that patients with RA are not resistant to the anabolic effects of exercise, and that for patients with RA, as for healthy individuals, an appropriate combination of PRT intensity and volume is required to produce beneficial changes in body composition (35).
Predictably, the increases in muscle mass elicited by our PRT intervention were associated with improvements in strength and objectively assessed function. Although these correlations are mostly moderate, indicating that other factors also contribute to the improvements in physical function induced by PRT in patients with RA (36, 37), this association between muscle hypertrophy and enhanced physical performance replicates the findings from our pilot study (5). Interestingly, given that muscle mass is thought to decline in the general population at approximately 6% per decade after the age of 50 years and strength by approximately 12–14% per decade over the same period (38), there is reasonable agreement from the mean gains we observed in ALM (8.4%) and KES (25%) following 24 weeks of PRT that these training effects are equivalent to the reversal of 14–20 years of sarcopenia. That PRT should have such a positive effect on function and disability in patients with RA is to be expected given the recent finding that both ALM and appendicular fat mass exert significant effects on HAQ score (1).
In common with most exercise intervention studies requiring volunteer subjects, the current study suffers from having a relatively biased sample, i.e., our patient cohort is less disabled than would be anticipated if outpatients were randomly selected. Despite this restriction, the incidence of significant muscle loss (cachexia) among subjects at baseline approached 60%, the incidence of obesity was 79%, and the incidence of cachectic-obesity (i.e., the coincidence of both conditions) was ∼36%. In the general elderly population, classification as either muscle wasted (sarcopenic) or obese significantly increases the likelihood of disability (39), and the coincidence of both (sarcopenic-obesity) independently increases the risk of disability in women 12 fold. It is notable that in the current study, PRT removed most of the subjects previously classified as cachectic and cachectic-obese from these high-risk categories.
The inability of PRT to change MDHAQ scores in the current study is consistent with results from other exercise intervention studies (12, 36, 40), and is likely to be due to the low disability of our patients and the relative insensitivity of this instrument to detect improvements in mildly disabled patients. Although the level of disability for our patients with RA was comparatively mild, it should be noted that, consistent with their reduced muscle mass and increased adiposity, performance of objective function tests by the PRT patients at baseline and the controls throughout was inferior to that of age- and sex-matched, sedentary, healthy individuals. Notably, performance of these tests, which were developed to assess the physical capacity of elderly people to perform activities of daily living (23), was normalized in patients with established RA by 24 weeks of PRT. Because in the current study habitual physical activity, diet, and disease activity remained unchanged, none of these factors can account for the improvements in body composition or function following PRT.
Despite the devastating consequences that impaired physical function has on patients with RA, society, and the economy, little research has been devoted to the metabolic changes that cause the muscle loss underlying much of this decrement (2, 8). This is regrettable because insights into the mechanisms of rheumatoid cachexia and its reversal should lead to improvements in patient treatment and outcome. To further this understanding, in the current study we tested our hypothesis that PRT exerts its anabolic effects in patients with RA, as it does in healthy individuals, primarily through an increase in mIGF-1 activity (14). Our data appear to support this proposed mechanism. The mIGF-1 levels in the 14 patients with RA from whom biopsy samples were taken were reduced relative to levels we observed previously in healthy, sedentary controls of a similar age (mean ± SD 2.78 ± 1.76 ng/mg total protein) (17). This is consistent with the diminished mIGF-1 levels identified in subjects with chronic renal failure (17, 19), chronic heart failure (16), chronic obstructive pulmonary disease (COPD) (18), and advanced aging (15); all of which are conditions characterized by muscle wasting. In turn, mIGF-1 and mIGFBP-3 levels in our patients with RA increased significantly in response to PRT. Although these results should be interpreted conservatively due to the low and uneven biopsy sample sizes, the effect size is large and this finding of augmented mIGF-1 levels with accompanying muscle hypertrophy has also been seen in frail, elderly subjects following PRT (15) and in patients with COPD after high-intensity training (18). Similarly, an increase in mIGFBP-3 accompanying training-induced hypertrophy has been described in patients with hemodialysis (41). In contrast, 12 weeks of high-intensity interval cycling that failed to increase muscle mass in patients with hemodialysis also failed to raise mIGF-1 or IGFBP-3 levels (19). Unlike muscle IGFs, and consistent with previous results in older adults (42, 43), including patients with RA (12), there was no effect of PRT on any of the measured components of the systemic IGF system in our patients.
To summarize, our results confirm that PRT is a safe and effective means of restoring muscle mass and functional capacity in patients with established, stable RA. Consequently, we advocate that, for appropriate patients, PRT programs similar to ours be included in disease management. We also provided a mechanistic insight into muscle anabolism in RA that could affect clinical and pharmaceutical approaches to treatment.