The beneficial effect of chronic muscular exercise on muscle fragility is increased by Prox1 gene transfer in dystrophic mdx muscle

Purpose. Greater muscle fragility is thought to cause the exhaustion of the muscle stem cells during successive degeneration/repair cycles, leading to muscle wasting and weakness in Duchenne muscular dystrophy. Chronic voluntary exercise can partially reduce the susceptibility to contraction induced-muscle injury, i.e., muscle fragility, as shown by a reduced immediate maximal force drop following lengthening contractions, in the dystrophic mdx mice. Here, we studied the effect of Prospero-related homeobox factor 1 gene ( Prox1) transfer (overexpression) on fragility in chronically exercised mdx mice, because Prox1 promotes slower type fibres in healthy mice and slower fibres are less fragile in mdx muscle. Methods . mdx mice received or not Prox1 transfer into the tibialis anterior muscle and performed voluntary running into a wheel during 1 month. We also performed Prox1 transfer in sedentary mdx mice. In situ maximal force production of the muscle in response to nerve stimulation was assessed before, during and after 10 lengthening contractions. Molecular and cellular parameters were also evaluated. Results . Interestingly, Prox1 transfer reduced the force drop following lengthening contractions in exercised mdx mice (p < 0.05 to 0.01), but not in sedentary mdx mice. It also increased the muscle expression of Myh7 (p < 0.001), MHC-2x (p < 0.01) and Trpc1 (p < 0.01), whereas it reduced that one of Myh4 (p < 0.001) and MHC-2b (p < 0.01) in exercised mdx mice. Moreover, Prox1 transfer decreased the maximal force (p < 0.01) before lengthening contraction in exercised mdx mice (p < 0.01), and reduced muscle weight (p < 0.0001) despite increased Mstn expression (p < 0.001). Conclusion . Our results indicate that the beneficial effect of Prox1 transfer on muscle fragility is only observed in chronically exercised mdx mice. Thus, Prox1 transfer combined to chronic exercise have the potential to substantially slow the progression of the dystrophic disease in the long term.

Specific modulation of corticomuscular coherence during submaximal voluntary isometric, shortening and lengthening contractions

During voluntary contractions, corticomuscular coherence (CMC) is thought to reflect a mutual interaction between cortical and muscle oscillatory activities, respectively measured by electroencephalography (EEG) and electromyography (EMG). However, it remains unclear whether CMC modulation would depend on the contribution of neural mechanisms acting at the spinal level. To this purpose, modulations of CMC were compared during submaximal isometric, shortening and lengthening contractions of the soleus (SOL) and the medial gastrocnemius (MG) with a concurrent analysis of changes in spinal excitability that may be reduced during lengthening contractions. Submaximal contractions intensity was set at 50% of the maximal SOL EMG activity. CMC was computed in the time–frequency domain between the Cz EEG electrode signal and the unrectified SOL or MG EMG signal. Spinal excitability was quantified through normalized Hoffmann (H) reflex amplitude. The results indicate that beta-band CMC and normalized H-reflex were significantly lower in SOL during lengthening compared with isometric contractions, but were similar in MG for all three muscle contraction types. Collectively, these results highlight an effect of contraction type on beta-band CMC, although it may differ between agonist synergist muscles. These novel findings also provide new evidence that beta-band CMC modulation may involve spinal regulatory mechanisms.

Prox1 gene transfer combined with voluntary exercise improves dystrophic muscle fragility in Mdx mice

Background Voluntary exercise can improve skeletal muscle fragility, i.e. higher susceptibility to contraction induced-injury, as shown by a greater force drop following lengthening contractions, in the dystrophic Mdx mice as compared to healthy mice with dystrophin. This beneficial effect is related to the activation of the calcineurin activation. Unfortunately, voluntary running only partly rescued fragility, so it would be interesting to combined the effects of exercise, for example, with those of others treatments activating the calcineurin pathway and promoting slow and more oxidative fibres. This is of particular interest because slow muscle fibres are apparently less affected and genetic or pharmacological treatments promoting slow and more oxidative fibres are been shown to be beneficial in the Mdx mice. Methods Here, we tested whether voluntary exercise (1 month of running in a wheel) combined with Prospero-related homeobox factor 1 gene ( Prox1) transfer would better improve functional dystrophic features in Mdx mice as compared to the voluntary exercise single approach. Prox1 is known to promote the promotion of slow contractile gene program in healthy muscle. Results We found that Prox1 transfer promoted slower molecular and functional contractile features in both voluntary exercised and sedentary Mdx mice. However, it improved fragility only in exercised Mdx mice. Moreover, Prox1 transfer reduced absolute maximal force production by causing reduction in muscle weight in both exercised and sedentary Mdx mice. Conclusion In conclusion, our results indicate that the beneficial effects of voluntary exercise and Prox1 transfer on fragility are additive in Mdx mice.

Neurophysiological responses and adaptation following repeated bouts of maximal lengthening contractions in young and older adults

A bout of maximal lengthening contractions is known to produce muscle damage, but confers protection against subsequent damaging bouts, with both tending to be lower in older adults. Neural factors contribute to this adaptation, but the role of the corticospinal pathway remains unclear. Twelve young (27 ± 5 yr) and 11 older adults (66 ± 4 yr) performed two bouts of 60 maximal lengthening dorsiflexions 2 weeks apart. Neuromuscular responses were measured preexercise, immediately postexercise, and at 24 and 72 h following both bouts. The initial bout resulted in prolonged reductions in maximal voluntary torque (MVC; immediately postexercise onward, P < 0.001) and increased creatine kinase (from 24 h onward, P = 0.001), with both responses being attenuated following the second bout ( P < 0.015), demonstrating adaptation. Smaller reductions in MVC following both bouts occurred in older adults ( P = 0.005). Intracortical facilitation showed no changes ( P ≥ 0.245). Motor-evoked potentials increased 24 and 72 h postexercise in young ( P ≤ 0.038). Torque variability ( P ≤ 0.041) and H-reflex size ( P = 0.024) increased, while short-interval intracortical inhibition (SICI; P = 0.019) and the silent period duration (SP) decreased ( P = 0.001) in both groups immediately postexercise. The SP decrease was smaller following the second bout ( P = 0.021), and there was an association between the change in SICI and reduction in MVC 24 h postexercise in young adults ( R = −0.47, P = 0.036). Changes in neurophysiological responses were mostly limited to immediately postexercise, suggesting a modest role in adaptation. In young adults, neural inhibitory changes are linked to the extent of MVC reduction, possibly mediated by the muscle damage–related afferent feedback. Older adults incurred less muscle damage, which has implications for exercise prescription. NEW & NOTEWORTHY This is the first study to have collectively assessed the role of corticospinal, spinal, and intracortical activity in muscle damage attenuation following repeated bouts of exercise in young and older adults. Lower levels of muscle damage in older adults are not related to their neurophysiological responses. Neural inhibition transiently changed, which might be related to the extent of muscle damage; however, the role of processes along the corticospinal pathway in the adaptive response is limited.

Reduced corticospinal responses in older compared with younger adults during submaximal isometric, shortening, and lengthening contractions

The aim of this study was to assess differences in motor performance, as well as corticospinal and spinal responses to transcranial magnetic and percutaneous nerve stimulation, respectively, during submaximal isometric, shortening, and lengthening contractions between younger and older adults. Fifteen younger [26 yr (SD 4); 7 women, 8 men] and 14 older [64 yr (SD 3); 5 women, 9 men] adults performed isometric and shortening and lengthening dorsiflexion on an isokinetic dynamometer (5°/s) at 25% and 50% of contraction type-specific maximums. Motor evoked potentials (MEPs) and H reflexes were recorded at anatomical zero. Maximal dorsiflexor torque was greater during lengthening compared with shortening and isometric contractions ( P < 0.001) but was not age dependent ( P = 0.158). However, torque variability was greater in older compared with young adults ( P < 0.001). Background electromyographic (EMG) activity was greater in older compared with younger adults ( P < 0.005) and was contraction type dependent ( P < 0.001). As evoked responses are influenced by both the maximal level of excitation and background EMG activity, the responses were additionally normalized {[MEP/maximum M wave (Mmax)]/root-mean-square EMG activity (RMS) and [H reflex (H)/Mmax]/RMS}. (MEP/Mmax)/RMS and (H/Mmax)/RMS were similar across contraction types but were greater in young compared with older adults ( P < 0.001). Peripheral motor conduction times were prolonged in older adults ( P = 0.003), whereas peripheral sensory conduction times and central motor conduction times were not age dependent ( P ≥ 0.356). These data suggest that age-related changes throughout the central nervous system serve to accommodate contraction type-specific motor control. Moreover, a reduction in corticospinal responses and increased torque variability seem to occur without a significant reduction in maximal torque-producing capacity during older age. NEW & NOTEWORTHY This is the first study to have explored corticospinal and spinal responses with aging during submaximal contractions of different types (isometric, shortening, and lengthening) in lower limb musculature. It is demonstrated that despite preserved maximal torque production capacity corticospinal responses are reduced in older compared with younger adults across contraction types along with increased torque variability during dynamic contractions. This suggests that the age-related corticospinal changes serve to accommodate contraction type-specific motor control.