Tue Kjølhede

Multiple sclerosis and progressive resistance training: a systematic review

Recently progressive resistance training (PRT) has been recognised as an effective tool in the rehabilitation of persons with multiple sclerosis (MS). The objective of this study was to systematically review the literature of PRT studies for persons with MS. A comprehensive literature search (PubMed, SveMed+, Embase, Cochrane, PEDro, SPORTDiscus and Bibliotek.dk) was conducted. Identified papers were rated according to the PEDro-scale. Sixteen studies were included and scored between 3 and 8 of 11 total points on the PEDro-scale, showing a general lack of blinding. Strong evidence regarding the beneficial effect of PRT on muscle strength was observed. Regarding functional capacity, balance and self-reported measures (fatigue, quality of life and mood) evidence is less strong, but the tendency is overall positive. Indications of an effect on underlying mechanisms such as muscle morphological changes, neural adaptations and cytokines also exist, but the studies investigating these aspects are few and inconclusive. PRT has a positive effect on muscle strength for persons with MS. Heterogeneous results exist regarding the effect on functional capacity and self-reported measures probably because of differences in training protocols, samples sizes, type and severity of MS. The area of underlying mechanisms deserves more attention in future research.

Muscle morphological and strength adaptations to endurance vs. resistance training

Farup, J, Kjølhede, T, Sørensen, H, Dalgas, U, Møller, AB, Vestergaard, PF, Ringgaard, S, Bojsen-Møller, J, and Vissing, K. Muscle morphological and strength adaptations to endurance vs. resistance training. J Strength Cond Res 26(2): 398–407, 2012—Fascicle angle (FA) is suggested to increase as a result of fiber hypertrophy and furthermore to serve as the explanatory link in the discrepancy in the relative adaptations in the anatomical cross-sectional area (CSA) and fiber CSA after resistance training (RT). In contrast to RT, the effects of endurance training on FA are unclear. The purpose of this study was therefore to investigate and compare the longitudinal effects of either progressive endurance training (END, n = 7) or RT (n = 7) in young untrained men on FA, anatomical CSA, and fiber CSA. Muscle morphological measures included the assessment of vastus lateralis FA obtained by ultrasonography and anatomical CSA by magnetic resonance imaging of the thigh and fiber CSA deduced from histochemical analyses of biopsy samples from m. vastus lateralis. Functional performance measures included &OV0312;;O2max and maximal voluntary contraction (MVC). The RT produced increases in FA by 23 ± 8% (p < 0.01), anatomical CSA of the knee extensor muscles by 9 ± 3% (p = 0.001), and fiber CSA by 19 ± 7% (p < 0.05). RT increased knee extensor MVC by 20 ± 5% (p < 0.001). END increased &OV0312;;O2max by 10 ± 2% but did not evoke changes in FA, anatomical CSA, or in fiber CSA. In conclusion, the morphological changes induced by 10 weeks of RT support that FA does indeed serve as the explanatory link in the observed discrepancy between the changes in anatomical and fiber CSA. Contrarily, 10 weeks of endurance training did not induce changes in FA, but the lack of morphological changes from END indirectly support the fact that fiber hypertrophy and FA are interrelated.

Neuromuscular adaptations to long-term progressive resistance training translates to improved functional capacity for people with multiple sclerosis and is maintained at follow-up

Background: Progressive resistance training (PRT) is acknowledged to effectively improve muscle strength for people with multiple sclerosis (PwMS), but diverging results exist regarding whether such improvements translates to improved functional capacity, possibly relating to insufficient duration and/or intensity in some previous studies. Objective: The purpose of this study was to evaluate potential changes in functional capacity and neuromuscular function after 24 weeks of supervised PRT, and whether improvements are maintained after an additional 24 weeks of self-guided exercise. Methods: This study was a randomised controlled trial, with a training group and a waitlist group undergoing supervised PRT for 24 weeks initially or after 24 weeks of habitual lifestyle, respectively. Functional capacity, isometric muscle strength of knee extensors and flexors, neural drive and thigh muscle cross-sectional area was measured at baseline, after 24 and 48 weeks. Results: The training group significantly improved neuromuscular function of the knee extensors and flexors, which translated to improvements in functional capacity. Furthermore, the improved functional capacity was maintained after 24 weeks of self-guided physical activity. The waitlist group produced similar patterns of changes after PRT. Conclusion: Compelling evidence is provided, that PRT performed over sufficiently long periods, improves functional capacity, likely due to neuromuscular adaptations.

AEROBIC INTENSITy AND pACING pATTERN DURING THE SIX-MINUTE WAlk TEST IN pATIENTS WITH MUlTIplE SClEROSIS

OBJECTIVE To examine the aerobic intensity level and pacing pattern during the 6-min walk test (6MWT) in persons with multiple sclerosis, taking into account time of day, fatigue, disability level and multiple sclerosis subtype. DESIGN Cross-sectional study. SUBJECTS/PATIENTS Eighty multiple sclerosis patients (Expanded Disability Status Scale, EDSS ≤ 6.5). METHODS Participants performed the 6MWT at 3 different time-points (morning, noon, afternoon) during 1 day. Heart rate and pacing strategy (distance covered every minute) were registered. A sub-group analysis determined the effects of fatigue, disability level and multiple sclerosis subtype. RESULTS The relative aerobic intensity was constant throughout the day (67 ± 10% of estimated maximal heart rate). In all sub-groups heart rate increased and distance walked declined after the first minute (p < 0.001). The mild EDSS sub-group showed a slightly larger increase throughout the 6MWT in heart rate development, while no differences were seen in sub-groups of fatigue and multiple sclerosis subtype. In most sub-groups walking speed was fastest in the first minute and constant during the final 4 minutes. CONCLUSION In patients with multiple sclerosis aerobic intensity is moderate during the 6MWT and unaffected by time of day. Disability may have some influence on aerobic intensity, but not on pacing strategy during the 6MWT, whereas neither fatigue nor multiple sclerosis subtype has any effect.

Relationship between muscle strength parameters and functional capacity in persons with mild to moderate degree multiple sclerosis

BACKGROUND Maximal muscle strength has been shown to be an important predictor of functional capacity for persons with multiple sclerosis (PwMS). Another muscle strength parameter known to be important for functional capacity in other patient groups is rate of force development (RFD) in knee extensors and flexors. This has not been investigated for PwMS. Thus, the purpose of this study was to investigate the relationship between RFD and maximal muscle strength of knee extensors and flexors and measures of functional capacity in PwMS. METHODS 35 PwMS (Expanded Disability Status Scale 2-4) underwent isokinetic dynamometry to determine RFD and maximal isometric and isokinetic muscle strength for both legs. Furthermore all participants performed timed 25 foot walk tests (T25FWT), two minute walk tests (2MWT), stairclimb tests and 5-time sit-to-stand (5STS) tests to determine functional capacity. Multiple linear regressions were performed to determine which muscle strength parameter would serve as a stronger predictor of walking performance. RESULTS Both RFD and maximal muscle strength correlated with functional capacity. Correlations were strongest for knee extensors and flexors of the weaker leg, while no clear ranking of the influence of the knee extensors vs. flexors on walking was evident. Multiple linear regressions showed that maximal isokinetic strength of the weaker leg is a better predictor for T25FWT and 2MWT performance than RFD. CONCLUSIONS Maximal muscle strength of the weaker leg is the better predictor of walking performance in persons with mild to moderate multiple sclerosis. RFD, although also important for functional capacity, is a less strong predictor. Maximal strength of the knee extensors, rather than the knee flexors, predicted performance in the stairclimb and 5STS tests.

Similar changes in muscle fiber phenotype with differentiated consequences for rate of force development: Endurance versus resistance training

Resistance training has been shown to positively affect the rate of force development (RFD) whereas there is currently no data on the effect of endurance training on RFD. Subjects completed ten weeks of either resistance training (RT, n=7) or endurance cycling (END, n=7). Pre and post measurements included biopsies obtained from m. vastus lateralis to quantify fiber phenotype and fiber area and isokinetic dynamometer tests to quantify maximal torque (Nm) and RFD (Nm/s) at 0-30, 0-50, 0-100 and 0-200ms during maximal isometric contraction for both knee extensors and flexors. Both groups increased the area percentage of type IIa fibers (p<.01) and decreased the area percentage of type IIx fibers (p=.05), whereas only RT increased fiber size (p<.05). RT significantly increased eccentric, concentric and isometric strength for both knee extensors and flexors, whereas END did not. RT increased 200ms RFD (p<.01) in knee flexor RFD and a tendency towards an increase at 100ms (p<.1), whereas tendencies towards decreases were observed for the END group at 30, 50 and 100ms (p<.1), resulting in RT having a higher RFD than END at post (p<.01). In conclusion, resistance training may be very important for maintaining RFD, whereas endurance training may negatively impact RFD.

Acute and chronic cytokine responses to resistance exercise and training in people with multiple sclerosis

Exercise is a well‐established part of rehabilitation for people with multiple sclerosis (PwMS), and it has been hypothesized to stimulate an anti‐inflammatory environment that might be disease modifying. Yet, investigations on exercise‐induced immune responses are scarce and generally not paying attention to the medical treatments of the patient. At present, PwMS are routinely enrolled in immunosuppressive medication, but exercise‐induced immunomodulatory effects have not been investigated under these circumstances. The objective of this study was to investigate the acute and chronic cytokines responses to resistance exercise training in medicated PwMS. Thirty‐five people with relapsing‐remitting multiple sclerosis (MS) treated with interferon (IFN)‐β, were randomized to a 24‐week progressive resistance training (PRT) or control group. Plasma interleukin (IL)‐1β, IL‐4, IL‐10, IL‐17F, IL‐23, tumor necrosis factor‐α and IFN‐γ were measured before and after 24 weeks of PRT. The acute effect was evaluated following standardized single‐bout resistance exercise in the untrained and the trained state. No changes were observed in resting cytokine levels after PRT. However, an indication of reduced IL‐17F secretion following resistance exercise was observed in the trained compared with the untrained state. This study suggests little acute and chronic effect of PRT on cytokine levels in IFN‐treated PwMS.

Can resistance training impact MRI outcomes in relapsing-remitting multiple sclerosis?

Background: Multiple sclerosis (MS) is characterised by accelerated brain atrophy, which relates to disease progression. Previous research shows that progressive resistance training (PRT) can counteract brain atrophy in other populations. Objective: To evaluate the effects of PRT by magnetic resonance imaging (MRI) and clinical measures of disease progression in people with MS. Methods: This study was a 24-week randomised controlled cross-over trial, including a Training (n = 18, 24 weeks of PRT followed by self-guided physical activity) and Waitlist group (n = 17, 24 weeks of habitual lifestyle followed by PRT). Assessments included disability measures and MRI (lesion load, global brain volume, percentage brain volume change (PBVC) and cortical thickness). Results: While the MS Functional Composite score improved, Expanded Disability Status Scale, lesion load and global brain volumes did not differ between groups. PBVC tended to differ between groups and higher absolute cortical thickness values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups for four areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior temporal sulcus. Conclusion: PRT seem to induce an increase in cortical thickness, indicating that PRT have a neuroprotective or even neuroregenerative effect in relapsing-remitting MS.

AMPK vs mTORC1 signaling: genuine exercise effects of differentiated exercise in humans. Response to letter to editor by Dr A. K. Yamada.

Substantial data exist that AMPK signaling is activated to drive catabolic metabolic processes (e.g., during energy-demanding exercise), while simultaneously possessing the ability to inactivate anabolic mTORC1driven energy-consuming protein synthesis, via TSC2 and/or raptor (Goodman et al., 2011). Conversely, nutrients and/or mechanical loading (during, e.g., resistance exercise) are well-established activators of mTORC1 signaling and protein synthesis (Hornberger, 2011), with the downstream S6K thought to also possess the ability to participate in simultaneous inactivation of AMPK (Aguilar et al., 2007). However, much of this knowledge is generated from in vitro or animal studies. As appreciated in a topical letter to editor by Dr A. K. Yamada (Yamada, 2011), the inherent heterogeneity and/or confounding factors, makes results from human exercise studies (comprising exercise as it is commonly practiced), less simplistic to interpret. As remarked, we therefore recently attempted to improve the degree of rigor in the design of a human exercise study addressing aforementioned differential exercise signaling, to control for effects of unfamiliar exercise, dietary status, diurnal rhythm and invasive procedures (Vissing et al., 2011). Accordingly, we employed (a) training-accustomed exercise subjects performing exercise by commonly practiced principles; (b) fasting protocol prior to, during, and after exercise; (c) an elaborate and strict absolute time course of tissue sampling; and (d) addition of a non-exercise control group. To address the reflections of Dr Yamada, unlike previous human exercise studies, our approach did in fact provide support for the hypothesis that Akt-independent mTORC1 signaling is switched on selectively by the mechanical strain inherent of heavy load resistance exercise (involving both eccentric and concentric modality), but not moderate-intensity endurance exercise (Vissing et al., 2011). Also according to an AMPK-mTORC1 switch hypothesis, our endurance exercise protocol switched on AMPK signaling and with reference to previous investigations, it is likely that AMPK simultaneously switched off mTORC1 signaling through TSC2 or raptor (Goodman et al., 2011; Hornberger, 2011). The very modest degree of AMPK activation after resistance exercise (which was not statistically different from endurance exercise), imply that exercise and postexercise metabolic demands after resistance exercise can actually be substantial enough to switch on AMPK signaling. Thus, it can be speculated that the limited time of recovery interspacing resistance exercise sets in our study (only 1.5 min between sets of 4 ¥ 12 repetition maximum in each of three consecutive leg exercises, to provoke hypertrophy signaling) accumulated into a substantial elevation in AMP/ATP ratio. Further support to this notion comes from the recent findings that endurance immediately followed by resistance exercise can enhance molecular signaling of mitochondrial biogenesis compared to endurance exercise alone (Wang et al., 2011). Furthermore, it can be speculated that the mechanical strain inherent of moderateintensity exercise of concentric modality (as performed during cycling) was insufficient to affect mechanotransducers enough to switch on mTORC1 signaling. In conclusion, although training status, dietary status, and choice of exercise protocols can all modulate signaling responses, resistance exercise may be able to produce more of an overlapping effect on signaling for mitochondrial biogenesis, than endurance exercise is able to produce overlapping effect on hypertrophy signaling.

Can aerobic exercise alleviate flu-like symptoms following interferon beta-1a injections in patients with multiple sclerosis?

BACKGROUND Flu-like symptoms (FLS) are common side effects of interferon beta (IFNß) treatment, and may affect the willingness to initiate therapy, the long-term acceptability, and the adherence to the treatment. Case reports suggest that aerobic exercise is able to markedly reduce FLS following IFNß-1a injections in persons with multiple sclerosis (PwMS). OBJECTIVE To test the hypothesis that aerobic exercise can alleviate FLS following IFNß-1a injections in PwMS, and secondarily to examine whether or not fluctuations in circulating cytokines provide a mechanism that can explain a potential positive effect. METHODS Seventeen PwMS who frequently experience FLS following IFNß-1a injections completed four days of testing. On two of the testing days they completed 35min of aerobic exercise on a bicycle-ergometer following IFNß-1a injection. On the two other testing days, no intervention took place following the injection. FLS were assessed pre-injection and 3h, 5h, 12h and 24h post-injection. Blood samples were taken pre-injection and 1h and 3h post-injection to determine levels of circulating interleukin 6 and 17 and IFNγ. The primary study endpoint was the comparison of the change in FLS severity from pre-injection to 5h post-injection between days with injection alone and days with injection followed by aerobic exercise. RESULTS FLS severity change was significantly lower on days with exercise compared to days with rest. IL6 was significantly increased 3h following IFNß-1a injection and exercise compared to 1h post and pre and when compared to the resting condition. Participants reported no adverse events in addition to FLS during the study period. CONCLUSION Data from this study suggest that moderate intensity aerobic exercise following IFNß-1a injections is safe and can alleviate the FLS severity in PwMS. Based on these results, 35min of aerobic exercise should be encouraged for PwMS who often experience FLS following IFNß-1a injections.