Carnosine and skeletal muscle dysfunction in a rodent multiple sclerosis model.

Muscle weakness and fatigue are primary manifestations of multiple sclerosis (MS), a chronic disease of the central nervous system. Interventions that enhance muscle function may improve overall physical well-being of MS patients. Recently, we described that levels of carnosine, an endogenous muscle dipeptide involved in contractile function and fatigue-resistance, are reduced in muscle tissue from MS patients and a monophasic rodent MS model (experimental autoimmune encephalomyelitis, EAE). In the present study, we aimed to (1) confirm this finding in a chronic EAE model, along with the characterization of structural and functional muscle alterations, and (2) investigate the effect of carnosine supplementation to increase/restore muscle carnosine levels and improve muscle function in EAE. We performed muscle immunohistochemistry and ex vivo contractility measurements to examine muscle structure and function at different stages of EAE, and following nutritional intervention (oral carnosine: 3, 15 or 30 g/L in drinking water). Immunohistochemistry revealed progressively worsening muscle fiber atrophy and a switch towards a fast-twitch muscle phenotype during EAE. Using ex vivo muscle contractility experiments, we observed reductions in muscle strength and contraction speed, but no changes in muscle fatigability of EAE mice. However, carnosine levels were unaltered during all stages of EAE, and even though oral carnosine supplementation dose-dependently increased muscle carnosine levels up to + 94% after 56 days EAE, this did not improve muscle function of EAE mice. In conclusion, EAE mice display significant, yet time-dependent, muscular alterations, and carnosine intervention does not improve muscle function in EAE.

Is maximal muscle strength and fatigability of three lower limb muscle groups associated with walking capacity and fatigability in multiple sclerosis? An exploratory study.

BACKGROUND: Both muscle fatigability and walking fatigability are prevalent in persons with MS (pwMS), but their associations remains unclear. The aim of this study was to examine the association of muscle strength and fatigability from both isometric and concentric protocols of three different muscle groups, and their association to walking capacity and walking fatigability. METHODS: Twenty-seven pwMS and 13 Healthy Controls (HC) were included in this exploratory study. All participants performed a six-minute walking test (6MWT), where the distance walked index (DWI) was calculated to measure walking fatigability with a cut-off score of -10%. In three different muscle groups (knee extensors (KE), knee flexors (KF), ankle dorsiflexors (DF)), isometric and concentric muscle fatigability protocols (FIisometric or FIconcentric) were used to quantify maximal voluntary contraction (MVC) and muscle fatigability. Pearson or Spearman correlation coefficients and linear regression models were calculated to establish the association between muscle strength/fatigability and walking capacity/fatigability. RESULTS: Higher MVCs values for all muscle groups were found in HC compared to pwMS (mainly those having walking fatigability) (p < 0.05). FIisometric of DF was lower in pwMS having walking fatigability compared to no walking fatigability. MVC of KE, KF and DF had a low to moderate association with walking capacity (range r = 0.52-0.56; p < 0.05) and walking fatigability in pwMS (range r-rs: 0.39-0.50; p<0.05). FIconcentric of KF and DF, but not of KE, were associated with walking fatigability (r = 0.39 and rs = 0.47, respectively; p < 0.05). In contrast, FIisometric for all muscle groups were not related to walking capacity or walking fatigability. CONCLUSION: MVC of KE, KF and DF are associated with walking capacity and walking fatigability, while concentric (but not isometric) muscle fatigability of KF and DF are associated with walking fatigability.

Periodized versus classic exercise therapy in Multiple Sclerosis: a randomized controlled trial.

BACKGROUND: Periodizing exercise interventions in Multiple Sclerosis (MS) shows good high intensity exercise training adherence. Whether this approach induces comparable training adaptations with respect to exercise capacity, body composition and muscle strength compared to conventional, linear progressive training programs however is not known. METHODS: Thirty-one persons with MS (all phenotypes, mean EDSS 2.3±1.3) were randomized into a twelve-week periodized (MSPER, n=17) or a classic endurance (MSCLA, n=14) training program. At baseline (PRE), exercise capacity (maximal exercise test, VO2max), body composition (DEXA) and muscle strength (Biodex®) were assessed. Classic, moderate intensity endurance training (60-80% HRmax, 5 training sessions/2w, 60min/session) was performed on a stationary bicycle. Periodized exercise included 4 recurrent 3-week cycles of alternated endurance training (week 1: endurance training as described above), high intense exercise (week 2: 3 sessions/w, 3 × 20s all-out sprints, 10min/session) and recovery weeks (week 3: one sprint session as described above). POST measurements were performed similar to baseline. Total exercise volume of both programs was expressed as total peak-effort training minutes. RESULTS: For MSCLA, total exercise volume included 1728 total peak-effort training minutes, whereas MSPER included only 736. Despite this substantially reduced training volume, twelve weeks of periodized training significantly (p<0.05) improved VO2max (+14%, p=0.001), workload (+20%) and time until exhaustion (+25%). Classic training significantly (p<0.05) improved workload (+10%) and time until exhaustion (+17%), but not VO2max (+5%, p=0.131). Pre-post improvements for VO2max were significantly higher in MSPER compared to MSCLA (p=0.046). CONCLUSION: These data show that despite substantially lower training time (57% less peak-effort training minutes), 12 weeks of periodized exercise training in persons with MS seems to induce larger improvements in parameters of exercise capacity compared to classic endurance training. We therefore recommend to further investigate the effect of training periodization on various functional rehabilitation measures in MS.

Periodized home-based training: A new strategy to improve high intensity exercise therapy adherence in mildly affected patients with Multiple Sclerosis.

INTRODUCTION: Although high intensity exercise therapy (HIT) in Multiple Sclerosis (MS) induces substantial effects, longer term compliance to such a training program is not evident. When embedded in a periodized, home-based training strategy, high intensity exercise therapy adherence may improve. This is explored first in mildly affected persons with MS. METHODS: Exercise capacity (maximal exercise test) and body composition (DEXA) of healthy controls (n = 22) and persons with MS (n = 23, EDSS: 1.9 ±â€¯1.1) were assessed at baseline (PRE). Next and within the context of an MS awareness project (climbing the Mont Ventoux, France), all participants were enrolled in a 6 m home-based periodized HIT oriented cycling program with remote (Polar® M200 activity tracker) supervision. Hereafter, POST measurements were performed similar to baseline. RESULTS: Six months of periodized and home-based HIT oriented training induced improvements in body weight (-3%, p = 0.008), BMI (-3%, p = 0.01), total mass (-2%, p = 0.023), VO2max (+ 5%, p = 0.016), workload (+ 11%, p = 0.001), time until exhaustion (+ 14%, p = 0.001), recovery heart rate (+ 4%, p = 0.04), lactate peak (+ 16%, p = 0.03) and RER (+ 4%, p = 0.04) in MS. Furthermore, all persons with MS safely reached the top of the Mont Ventoux, except for two. CONCLUSION: The applied 6 m periodized, home-based and HIT-oriented cycling program provided good therapy adherence with similar improvements in exercise capacity compared to healthy controls. Furthermore, this exercise regimen trained mildly-affected persons with MS adequately to climb the Mont Ventoux.

Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance.

Oxidative phosphorylation in mitochondria is responsible for 90% of ATP synthesis in most cells. This essential housekeeping function is mediated by nuclear and mitochondrial genes encoding subunits of complex I to V of the respiratory chain. Although complex IV is the best studied of these complexes, the exact function of the striated muscle-specific subunit COX6A2 is still poorly understood. In this study, we show that Cox6a2-deficient mice are protected against high-fat diet-induced obesity, insulin resistance and glucose intolerance. This phenotype results from elevated energy expenditure and a skeletal muscle fiber type switch towards more oxidative fibers. At the molecular level we observe increased formation of reactive oxygen species, constitutive activation of AMP-activated protein kinase, and enhanced expression of uncoupling proteins. Our data indicate that COX6A2 is a regulator of respiratory uncoupling in muscle and we demonstrate that a novel and direct link exists between muscle respiratory chain activity and diet-induced obesity/insulin resistance.

The effect of muscle length on force depression after active shortening in soleus muscle of mice.

Isometric muscle force after active shortening is reduced [force depression (FD)]. The mechanism is incompletely understood but work delivered during shortening has been suggested to be the main determinant of FD. However, whether muscle length affects the sensitivity of FD to work is unknown, although this information might add to the understanding of the phenomenon. The aim of this study is to investigate the length dependence of the FD/work ratio (Q). Therefore, isometric force production (ISO) of 10 incubated mouse soleus muscles was compared to isometric force after 0.6, 1.2, and 2.4 mm shortening (IAS) at different end lengths ranging from L(0) - 3 to L(0) + 1.8 mm in steps of 0.6 mm. FD was calculated as the force difference between an ISO and IAS contraction at the same activation time (6 s) and end length. We confirm the strong relation between FD and work at L(0) (R² = 0.92) and found that FD is length dependent with a maximum of 8.8 ± 0.3% at L(0) + 1.2 mm for 0.6 mm shortening amplitude. Q was only constant for short muscle lengths (<85% L(0)) but increased exponentially with increasing muscle length. The observed length dependence of Q indicates that FD is not only determined by work produced during shortening but also by a length-dependent factor, possibly actin compliance, which should be incorporated in any mechanism explaining FD.

Shortening amplitude affects the incomplete force recovery after active shortening in mouse soleus muscle.

Compared to isometric contraction, the force producing capacity of muscle is reduced (force depression, FD) after a work producing shortening phase. It has been suggested that FD results from an inhibition of cross-bridge binding. Because the rate constants of the exponential force (re)development are thought to be primarily determined by cross-bridge attachment/detachment rate, we aimed to investigate the components of force redevelopment (REDEV) after 0.6, 1.2 and 2.4mm shortening, resulting in varying amounts of FD (from about 5% to about 16%), in mouse soleus muscle (n=11). Compared to isometric force development (DEV), the time to reach steady-state during REDEV was about 3 times longer (370 versus 1261ms) increasing with increasing amplitude. Contrary to a single, a double exponential function with one component set equal to the rate constant of DEV (14.3s(-1)), accurately described REDEV (RMS<0.8%). The rate constant of the additional slow component decreased with increasing shortening amplitude and was associated with work delivered during shortening (R(2)=0.75) and FD (R(2)=0.77). We concluded that a work related slow exponential component is induced to the trajectory of incomplete force recovery after shortening, causing FD. These results suggest that after shortening, aside from cross-bridges with normal attachment/detachment rate, cross-bridges with reduced cycling rate are active.

Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism.

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.