Time matters: Early-phase multiple sclerosis is accompanied by considerable impairments across multiple domains.

Impairments across multiple domains are a disabling consequence of multiple sclerosis (MS). Originating from preventive medical strategies, the "time matters"-perspective has become a focal point when treating MS. In particular, early detection of physical and cognitive deficits, along with deficits in patient-reported outcomes seems crucial to further optimize both pharmacological and non-pharmacological MS treatment strategies. Therefore, this topical review investigates the level of impairments across multiple domains (physical function, cognitive function, and patient-reported outcomes) in the early stage of MS (⩽5 years since diagnosis, including clinically isolated syndrome (CIS)), when compared to matched healthy controls. Even at early disease stages, studies show impairments corresponding to 8%-34% and small-to-large numerical effect sizes (0.35-2.85) in MS/CIS patients across domains. This evidence call for early screening programs along with early interventions targeting the multiple impaired domains. This further highlights the importance of preventive initiatives preserving and/or restoring physical and cognitive reserve capacity if possible.

Plasma brain-derived neurotrophic factor (BDNF) and sphingosine-1-phosphat (S1P) are NOT the main mediators of neuroprotection induced by resistance training in persons with multiple sclerosis-A randomized controlled trial.

Resistance training (RT) has been shown to elicit neuroprotective effects in persons with multiple sclerosis (pwMS). Brain-derived neurotrophic factor (BDNF) and Sphingosine-1-phosphat (S1P) have been put forward as potent mediators of the neuroprotective effects induced by RT. However, while increases have been shown in acute and chronic circulating BDNF levels in pwMS following aerobic exercise alone or in combination with other exercise regimes, no studies have examined this in response to RT. As a novel 'proof-of-concept' approach, we therefore examined the effects of 24 weeks of RT on acute and chronic circulating BDNF and S1P levels in the same pwMS whom our group had previously observed RT-induced neuroprotective effects in (i.e. increased cortical thickness and preservation of whole brain volume). A total of n = 30 relapsing-remitting pwMS were randomized into a training group (TG: 24 weeks of progressive high intensity resistance training, 2 sessions per week; n = 16, age 44[40:51] years, EDSS score 3.0[2.0:3.5] (median[IQR]) or a control group (CG: 24 weeks of habitual lifestyle; n = 14, age 45[37:47] years, EDSS score 3.0[2.5:3.5]). Plasma levels of BDNF and S1P were assessed by ELISA kits before and after the 24-week intervention period. No within- or between group changes were observed in acute or chronic circulating levels of BDNF. A substantial proportion of the participants had S1P levels below the detection limit, yet no within- or between changes were observed in chronic S1P plasma levels in the remaining samples. Thus, the present findings do not support that circulating plasma BDNF or S1P levels are the main mediators of the neuroprotective effects previously reported in the same group of pwMS.

Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial.

The purpose of the study was to evaluate whether testosterone replacement therapy improves muscle mechanical and physical function in addition to increasing lean leg mass and total lean body mass in aging men with type 2 diabetes and lowered bio-available testosterone (BioT) levels. Thirty-nine men aged 50-70 years with type 2 diabetes and BioT levels <7.3 nmol/L were included from an academic tertiary-care medical center. Patients were randomized to testosterone gel (testosterone replacement therapy, n = 20) or placebo (n = 19) for 24 weeks, applying a double-blinded design. Muscle mechanical function was assessed by Nottingham Leg Rig (leg extension power) and isokinetic dynamometry (knee extensor maximal isometric contraction, rate of force development (RFD100), maximal dynamic contraction (Dyn180)). Physical function was assessed by gait speed. Body composition was assessed by whole body dual-energy X-ray absorptiometry (total lean body mass, lean leg mass, total fat mass, leg fat mass). Levels of total testosterone (TotalT), BioT, free testosterone (FreeT), and sex hormone-binding globulin were measured from fasting blood samples. Coefficients (b) represent the placebo-controlled mean effect of intervention. Maximal isometric contraction (b = 18.4 Nm, p = 0.039), RFD100 (b = 195.0 Nm/s, p = 0.017) and Dyn180 (b = 10.2 Nm, p = 0.019) increased during testosterone replacement therapy compared with placebo. No changes were observed in leg power or gait speed. Total lean body mass (b = 1.9 kg, p = 0.001) and lean leg mass (b = 0.5 kg, p < 0.001) increased, while total fat mass (b = -1.3 kg, p = 0.009) and leg fat mass (b = -0.7 kg, p = 0.025) decreased during testosterone replacement therapy compared with placebo. Total T (b = 14.5 nmol/L, p = 0.056), BioT (b = 7.6 nmol/L, p = 0.046), and FreeT (b = 0.32 nmol/L, p = 0.046) increased during testosterone replacement therapy compared with placebo, while sex hormone-binding globulin (n = -2 nmol/L, p = 0.030) decreased. Knee extensor muscle mechanical function was preserved, and body composition improved substantially during testosterone replacement therapy for 24 weeks compared with placebo, whereas physical function (gait speed) was unchanged in aging men with type 2 diabetes and lowered BioT levels.

Influence of Resistance Training on Neuromuscular Function and Physical Capacity in ALS Patients.

OBJECTIVES: The present study aimed to explore the effect of resistance training in patients with amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motor neuron loss and muscle weakness. MATERIALS AND METHODS: Following a 12-week "lead-in" control period, a population of ALS patients from Funen, Denmark, completed a 12-week resistance training program consisting of 2-3 sessions/week. Neuromuscular function (strength and power) and voluntary muscle activation (superimposed twitch technique) were evaluated before and after both control and training periods. Physical capacity tests (chair rise and timed up and go), the revised ALS functional rating scale (ALSFRS-R) scores, and muscle cross sectional area (histology) were also assessed. RESULTS: Of twelve ALS patients assessed for eligibility, six were included and five completed the study. Training did not significantly affect the ALSFRS-R score, and loss of neuromuscular function (strength and power) increased following the training period. However, an improved functionality (chair rise) and an increase in greatly hypertrophied type II fibres combined with an increase in atrophied fibres following the training period compared to the control period were observed. CONCLUSION: In this small study, the present form of resistance training was unable to attenuate progressive loss of neuromuscular function in ALS, despite some changes in physical capacity and morphology.

Muscle strength and power in persons with multiple sclerosis - A systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease in the central nervous system which causes a number of physical symptoms including impairments of muscle mechanical function (muscle strength, muscle power and explosive muscle strength (~rate of force development, RFD)). However, a full overview of the existing knowledge regarding muscle mechanical function in persons with MS (PwMS) is still pending. OBJECTIVES: To systematically review 1) the psychometric properties of isokinetic dynamometry testing in PwMS, and 2) studies comparing muscle mechanical function in PwMS to matched healthy controls (HC). In addition, a meta-analysis will evaluate 3) the effects of progressive resistance training on muscle mechanical function in PwMS. METHODS: A systematic literature search was performed in eight databases. To be included in the review, the study had to 1) enroll participants with a confirmed diagnosis of MS; 2) assess muscle mechanical function 3) had undergone peer-review. The psychometric properties of isokinetic dynamometry were reviewed with respect to validity, reliability, and responsiveness. Comparison of muscle strength between PwMS and HC was performed across contraction velocities, contraction modes and muscle groups, as were the rate of force development. The effects of progressive resistance training on muscle mechanical function were evaluated in a meta-analysis using a random effects model and standardized mean difference (SMD). RESULTS: A total of four, twenty-four, and ten studies were identified for aim 1, 2, and 3, respectively. High Intraclass correlations coefficients (range: 0.87-0.99) for isokinetic dynamometry was reported when assessing knee extensor and knee flexor muscle strength independent of contraction velocity. Compared to match HC, PwMS display impaired muscle strength, power and explosive muscle strength. Muscle strength impairments were most pronounced during maximal moderate to fast dynamic muscle contractions of the lower extremities. Progressive resistance training has a small but significant effect on muscle mechanical function in PwMS (SMD=0.45, 95% CI: 0.18-0.72, p=0.001). CONCLUSIONS: The present review showed that 1) isokinetic dynamometry has a high reliability in PwMS; 2) muscle strength, power and rate of force development is impaired in PwMS compared to HC, and muscle strength impairments are most pronounced during maximal moderate to fast dynamic muscle contractions of the lower extremities; and 3) progressive resistance training can improve muscle mechanical function in PwMS. Future studies should evaluate progressive resistance training designed to optimize maximal moderate to fast dynamic muscle contractions of the lower extremities.

Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults - A randomized controlled trial.

Brain-derived neurotrophic factor (BDNF) is a potential important factor involved in neuroplasticity, and may be a mediator for eliciting adaptations in neuromuscular function and physical function in older individuals following physical training. As power training taxes the neural system to a very high extent, it may be particularly effective in terms of eliciting increases in systemic BDNF levels. We examined the effects of 12weeks of power training on mature BDNF (mBDNF) and total BDNF (tBDNF) in mobility-limited older adults from the Healthy Ageing Network of Competence (HANC) study. We included 47 older men and women: n=22 in the training group (TG: progressive high intensity power training, 2 sessions per week; age 82.7±5.4years, 55% women) and n=25 in the control group (CG: no interventions; age 82.2±4.5years, 76% women). Following overnight fasting, basal serum levels of mBDNF and tBDNF were assessed (human ELISA kits) at baseline and post-intervention. At baseline, mBDNF and tBDNF levels were comparable in the two groups, TG and CG. Post-intervention, no significant within-group or between-group changes were observed in mBDNF or tBDNF. Moreover, when divided into responder tertiles based upon changes in mBDNF and tBDNF (i.e. decliners, maintainers, improvers), respectively, comparable findings were observed for TG and CG. Altogether, basal systemic levels of serum mBDNF and tBDNF are not affected in mobility-limited older adults following 12-weeks of power training, and do not appear to be a major mechanistic factor mediating neuroplasticity in mobility-limited older adults.

Repeated high-intensity exercise modulates Ca(2+) sensitivity of human skeletal muscle fibers.

The effects of short-term high-intensity exercise on single fiber contractile function in humans are unknown. Therefore, the purposes of this study were: (a) to access the acute effects of repeated high-intensity exercise on human single muscle fiber contractile function; and (b) to examine whether contractile function was affected by alterations in the redox balance. Eleven elite cross-country skiers performed four maximal bouts of 1300 m treadmill skiing with 45 min recovery. Contractile function of chemically skinned single fibers from triceps brachii was examined before the first and following the fourth sprint with respect to Ca(2+) sensitivity and maximal Ca(2+) -activated force. To investigate the oxidative effects of exercise on single fiber contractile function, a subset of fibers was incubated with dithiothreitol (DTT) before analysis. Ca(2+) sensitivity was enhanced by exercise in both MHC I (17%, P < 0.05) and MHC II (15%, P < 0.05) fibers. This potentiation was not present after incubation of fibers with DTT. Specific force of both MHC I and MHC II fibers was unaffected by exercise. In conclusion, repeated high-intensity exercise increased Ca(2+) sensitivity in both MHC I and MHC II fibers. This effect was not observed in a reducing environment indicative of an exercise-induced oxidation of the human contractile apparatus.

Aging impairs the recovery in mechanical muscle function following 4 days of disuse.

As aged individuals are frequently exposed to short-term disuse caused by disease or musculoskeletal injury, it is important to understand how short-term disuse and subsequent retraining affect lower limb mechanical muscle function. The purpose of the present study was, therefore, to investigate the effect of 4 days of lower limb disuse followed by 7 days of active recovery on mechanical muscle function of the knee extensors in young (24.3±0.9 years, n=11) and old (67.2±1.0 years, n=11) recreationally active healthy males. Slow and moderate dynamic muscle strength were assessed using isokinetic dynamometry (60 and 180° s(-1), respectively) along with isometric muscle strength and rapid muscle force capacity examined as contractile rate of force development (RFD), Impulse, and relative RFD (rRFD) during the initial phase of contraction (100 ms time interval relative to onset of contraction). Prior to disuse, marked age-related differences (p<0.05) were observed in isometric and dynamic muscle strength (~35%) as well as in RFD and Impulse (~39%). Following disuse, young and old individuals experienced comparable decrements (p<0.05) in isometric strength (~9%), slow dynamic strength (~13%), and RFD and Impulse (~19%), whereas old individuals only experienced decrements (p<0.05) in moderate dynamic strength (12%) and rRFD (~17%). Following recovery, all measures of mechanical muscle function were restored in young individuals compared to pre-disuse values, while isometric, slow and moderate dynamic muscle strength remained suppressed (p<0.05) in old individuals (~8%) along with a tendency to suppressed RFD100 (p=0.068). In conclusion, 4 days of lower limb disuse led to marked decrements in knee extensor mechanical muscle function in both young and old individuals, yet with greater decrements observed in moderate dynamic strength and rapid muscle force capacity in old individuals. While 7 days of recovery - including free ambulation, one test session and a single session of strength training - was sufficient to restore mechanical muscle function in young individuals, old individuals appeared to have an impaired ability to fully recover as evidenced by suppressed values of isometric and dynamic muscle strength and rapid muscle force capacity.

Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle.

Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61-74 yrs) and 11 young (YM: mean age 24.4, range 21-30 yrs) males. Measures of myofibre area (MFA), Pax7-positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7-positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7-positive cells, and had more Pax7-positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age-related differences were observed in mRNA expression of IGF-1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down-regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age-related difference in muscle mass recovery.

Transient impairments in single muscle fibre contractile function after prolonged cycling in elite endurance athletes.

AIM: Prolonged muscle activity impairs whole-muscle performance and function. However, little is known about the effects of prolonged muscle activity on the contractile function of human single muscle fibres. The purpose of this study was to investigate the effects of prolonged exercise and subsequent recovery on the contractile function of single muscle fibres obtained from elite athletes. METHODS: Nine male triathletes (26 ± 1 years, 68 ± 1 mL O2  min(-1) kg(-1) , training volume 16 ± 1 h week(-1) ) performed 4 h of cycling exercise (at 73% of HRmax ) followed by 24 h of recovery. Biopsies from vastus lateralis were obtained before and following 4 h exercise and following 24 h recovery. Measurements comprised maximal Ca(2+) -activated specific force and Ca(2+) sensitivity of slow type I and fast type II single muscle fibres, as well as cycling peak power output. RESULTS: Following cycling exercise, specific force was reduced to a similar extent in slow and fast fibres (-15 and -18%, respectively), while Ca(2+) sensitivity decreased in fast fibres only. Single fibre-specific force was fully restored in both fibre types after 24 h recovery. Cycling peak power output was reduced by 4-9% following cycling exercise and fully restored following recovery. CONCLUSION: This is the first study to demonstrate that prolonged cycling exercise transiently impairs specific force in type I and II fibres and decreases Ca(2+) sensitivity in type II fibres only, specifically in elite endurance athletes. Further, the changes in single fibre-specific force induced by exercise and recovery coincided temporally with changes in cycling peak power output.

The effects of immobilization on the mechanical properties of the patellar tendon in younger and older men.

BACKGROUND: It remains unknown if inactivity changes the mechanical properties of the human patellar tendon in younger and older healthy persons. The purpose was to examine the effects of short-term unilateral immobilization on the structural and mechanical properties of the patellar tendon in older men and younger men, in vivo. METHODS: Eight older men and eight younger men underwent 14 days of unilateral immobilization. All individuals were assessed on both sides before and after the intervention. MRI was used to assess whole patellar tendon dimensions. The mechanical properties of the patellar tendon were assessed using simultaneous force and ultrasonographic measurements during isometric ramp contractions. FINDINGS: In older men, tendon stiffness [Pre: mean 2949 (SD 799) vs. Post: mean 2366 (SD 774) N mm(-1), P<0.01] and Young's Modulus [Pre: mean 1.2 (SD 0.3) vs. Post: mean 1.0 (SD 0.3) GPa, P<0.05] declined with immobilization on the immobilized side. On the control side, tendon stiffness [Pre: mean 3340 (SD 1209) vs. Post: mean 2230 (SD 503), P<0.01] and Young's Modulus [Pre: mean 1.5 (SD 0.4) vs. Post: mean 0.9 (SD 0.3) GPa, P<0.05] also decreased with immobilization. In younger men, tendon stiffness [Pre: 3622 (SD 1760) vs. Post: mean 2910 (SD 1528) N mm(-1), P<0.01] and Young's Modulus [Pre: mean 1.7 (SD 1.1) vs. Post: mean 1.4 (SD 0.8) GPa, P<0.05] decreased only on the immobilized side. INTERPRETATION: Short-term immobilization led to impaired mechanical properties of the patellar tendon on the immobilized side in both younger men and older men, which can influence the function of the muscle-tendon complex.

Effects of aging on human skeletal muscle after immobilization and retraining.

Inactivity is a recognized compounding factor in sarcopenia and muscle weakness in old age. However, while the negative effects of unloading on skeletal muscle in young individuals are well elucidated, only little is known about the consequence of immobilization and the regenerative capacity in elderly individuals. Thus the aim of this study was to examine the effect of aging on changes in muscle contractile properties, specific force, and muscle mass characteristics in 9 old (61-74 yr) and 11 young men (21-27 yr) after 2 wk of immobilization and 4 wk of retraining. Both young and old experienced decreases in maximal muscle strength, resting twitch peak torque and twitch rate of force development, quadriceps muscle volume, pennation angle, and specific force after 2 wk of immobilization (P < 0.05). The decline in quadriceps volume and pennation angle was smaller in old compared with young (P < 0.05). In contrast, only old men experienced a decrease in quadriceps activation. After retraining, both young and old regained their initial muscle strength, but old had smaller gains in quadriceps volume compared with young, and pennation angle increased in young only (P < 0.05). The present study is the first to demonstrate that aging alters the neuromuscular response to short-term disuse and recovery in humans. Notably, immobilization had a greater impact on neuronal motor function in old individuals, while young individuals were more affected at the muscle level. In addition, old individuals showed an attenuated response to retraining after immobilization compared with young individuals.