Local and systemic transcriptomic responses from acute exercise induced muscle damage of the human knee extensors.

Skeletal muscle is adaptable to a direct stimulus of exercise-induced muscle damage (EIMD). Local muscle gene networks and systemic circulatory factors respond to EIMD within days, mediating anti-inflammation and cellular proliferation. Here we show in humans that local EIMD of one muscle group is associated with a systemic response of gene networks that regulate muscle structure and cellular development in nonlocal homologous muscle not directly altered by EIMD. In the nondominant knee extensors of seven males, EIMD was induced through voluntary contractions against an electric motor that lengthened muscles. Neuromuscular assessments, vastus lateralis muscle biopsies, and blood draws occurred 2 days prior and 1 and 2 days after the EIMD intervention. From the muscle and blood plasma samples, RNA-Seq measured transcriptome changes of differential expression using bioinformatic analyses. Relative to the time of the EIMD intervention, local muscle that was mechanically damaged had 475 genes differentially expressed, as compared with 33 genes in the nonlocal homologous muscle. Gene and network analysis showed that activity of the local muscle was related to structural maintenance, repair, and energetic processes, whereas gene and network activities of the nonlocal muscle (that was not directly modified by the EIMD) were related to muscle cell development, stress response, and structural maintenance. Altered expression of two novel miRNAs related to the EIMD response supported that systemic factors were active. Together, these results indicate that the expression of genes and gene networks that control muscle contractile structure can be modified in response to nonlocal EIMD in humans.

Nerve dysfunction leads to muscle morphological abnormalities in chronic inflammatory demyelinating polyneuropathy assessed by MRI.

Neuropathic features of chronic inflammatory demyelinating polyneuropathy (CIDP) have been well documented, however very little is known about the implication of this neuropathy on skeletal muscle, and whether nerve lesions in CIDP lead to uniform disruptions in skeletal muscles. In this study, we assessed the triceps surae complex, using magnetic resonance imaging (MRI) in a group (n = 10) of CIDP patients compared with a healthy age-matched control group (n = 9). MRI (T1 and T2) of the leg musculature as well as plantar flexion strength measurements were obtained from both groups. CIDP patients compared with controls had ∼28% lower plantar flexion strength and ∼19% less total muscle volume (T1) of the triceps surae. When strength was normalized to fat corrected triceps surae volume CIDP patients were ∼30% weaker than controls. Relaxation times from the T2 scans were significantly longer in CIDP with the soleus, medial head of gastrocnemius and lateral head of gastrocnemius showing ∼37%, ∼38% and ∼26% longer relaxation times, respectively. CIDP patients were significantly weaker compared to controls and despite normalizing strength to total triceps surae contractile tissue volume this difference remained. CIDP patients had significantly longer T2 times, reflecting increased noncontractile tissue infiltration. These results indicate reduced muscle quantity and quality as a result of alterations in axonal function. Furthermore, when present study results are considered together with a prior report on the anterior compartment (Gilmore et al. 2016, Muscle Nerve 3:413-420), it is clear that both anterior and posterior leg compartments are affected similarly in CIDP despite different terminal nerve innervation and functional properties. Clin. Anat. 32:77-84, 2019. © 2019 Wiley Periodicals, Inc.

Human motor unit characteristics of the superior trapezius muscle with age-related comparisons.

Current understanding of human motor unit (MU) control and aging is mostly derived from hand and limb muscles that have spinal motor neuron innervations. The aim here was to characterize and test whether a muscle with a shared innervation supply from brainstem and spinal MU populations would demonstrate similar age-related adaptations as those reported for other muscles. In humans, the superior trapezius (ST) muscle acts to elevate and stabilize the scapula and has primary efferent supply from the spinal accessory nerve (cranial nerve XI) located in the brainstem. We compared electrophysiological properties obtained from intramuscular and surface recordings between 10 young (22-33 yr) and 10 old (77-88 yr) men at a range of voluntary isometric contraction intensities (from 15 to 100% of maximal efforts). The old group was 41% weaker with 43% lower MU discharge frequencies compared with the young (47.2 ± 9.6 Hz young and 26.7 ± 5.8 Hz old, P < 0.05) during maximal efforts. There was no difference in MU number estimation between age groups (228 ± 105 young and 209 ± 89 old, P = 0.33). Furthermore, there were no differences in needle detected near fiber (NF) stability parameters of jitter or jiggle. The old group had lower amplitude and smaller area of the stimulated compound muscle action potential and smaller NF MU potential area with higher NF counts. Thus, despite age-related ST weakness and lower MU discharge rates, there was minimal evidence of MU loss or compensatory reinnervation.NEW & NOTEWORTHY The human superior trapezius (ST) has shared spinal and brainstem motor neuron innervation providing a unique model to explore the impact of aging on motor unit (MU) properties. Although the ST showed higher MU discharge rates compared with most spinally innervated muscles, voluntary strength and mean MU rates were lower in old compared with young at all contraction intensities. There was no age-related difference in MU number estimates with minimal electrophysiological evidence of collateral reinnervation.

Reduced brain glutamine in female varsity rugby athletes after concussion and in non-concussed athletes after a season of play.

The purpose of this study was to use non-invasive proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) to monitor changes in prefrontal white matter metabolite levels and tissue microstructure in female rugby players with and without concussion (ages 18-23, n = 64). Evaluations including clinical tests and 3 T MRI were performed at the beginning of a season (in-season) and followed up at the end of the season (off-season). Concussed athletes were additionally evaluated 24-72 hr (n = 14), three months (n = 11), and six months (n = 8) post-concussion. Reduced glutamine at 24-72 hr and three months post-concussion, and reduced glutamine/creatine at three months post-concussion were observed. In non-concussed athletes (n = 46) both glutamine and glutamine/creatine were lower in the off-season compared to in-season. Within the MRS voxel, an increase in fractional anisotropy (FA) and decrease in radial diffusivity (RD) were also observed in the non-concussed athletes, and correlated with changes in glutamine and glutamine/creatine. Decreases in glutamine and glutamine/creatine suggest reduced oxidative metabolism. Changes in FA and RD may indicate neuroinflammation or re-myelination. The observed changes did not correlate with clinical test scores suggesting these imaging metrics may be more sensitive to brain injury and could aid in assessing recovery of brain injury from concussion.

Reductions in muscle quality and quantity in chronic inflammatory demyelinating polyneuropathy patients assessed by magnetic resonance imaging.

INTRODUCTION: Weakness in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) may be caused by decreases in muscle quantity and quality, but this has not been explored. METHODS: Twelve patients with CIDP (mean age 61 years) and 10 age-matched (mean age 59 years) control subjects were assessed for ankle dorsiflexion strength, and two different MRI scans (T1 and T2) of leg musculature. RESULTS: Isometric strength was 36% lower in CIDP patients compared with controls. Tibialis anterior muscle volumes of CIDP patients were smaller by ∼17% compared with controls, and non-contractile tissue volume was ∼58% greater in CIDP patients. When normalized to total muscle or corrected contractile volume, strength was ∼29% and ∼18% lower, respectively, in CIDP patients. DISCUSSION: These results provide insight into the structural integrity of muscle contractile proteins and pathologic changes to whole-muscle tissue composition that contribute to impaired muscle function in CIDP. Muscle Nerve 58: 396-401, 2018.

Effect of very old age on anconeus motor unit loss and compensatory remodelling.

INTRODUCTION: It is not known how the process of compensatory remodeling through collateral reinnervation continues into very old age (>80 years) or whether there is a limit to effective motor unit (MU) reinnervation. Therefore, we explore electrophysiological properties related to motor unit number estimates (MUNEs) in very old participants (79-90 years of age) compared with young controls (25-29 years of age). METHODS: Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyography information from the anconeus to derive a MUNE. RESULTS: Young participants had a MUNE of ∼38 and ∼25 at 30% and 50% root mean squared maximum voluntary contraction (RMSMVC ) with surface motor unit potentials (S-MUPs) of ∼145 µV and 236 µV, respectively. Older participants had a MUNE of ∼23 and ∼16 at 30% and 50% RMSMVC with S-MUPs of 168 µV and 232 µV, respectively. DISCUSSION: In this muscle, an age limit to successful remodeling through collateral reinnervation, to compensate for the presumed ongoing losses of MUs, may have been surpassed. Muscle Nerve 57: 659-663, 2018.

Motor unit number estimation and neuromuscular fidelity in 3 stages of sarcopenia.

INTRODUCTION: Loss of motor units (MUs) and alterations in MU properties are major factors in development of sarcopenia. The purpose of this study was to compare MU properties among 3 groups categorized as either pre-sarcopenic (n = 7), sarcopenic (n = 7), or severely sarcopenic (n = 5), all with similarly aged subjects (75-82 years). METHODS: Using decomposition-enhanced quantitative electromyography, MU number estimates and neuromuscular stability measures of near-fiber (NF) jitter and jiggle were derived in addition to contractile properties of ankle dorsiflexors. RESULTS: MU number estimates were similar across groups; however, maximal voluntary strength in the severe sarcopenia group was 27% and 37% less than the sarcopenic and pre-sarcopenic groups, respectively. Moreover, NF jiggle was 31% greater in the severe group compared with pre-sarcopenia, NF jitter was 43% greater in the severe group compared with the pre-sarcopenic group. CONCLUSION: Unlike MU number estimates, strength and MU stability differed across groups and related to degree of sarcopenia. Muscle Nerve 55: 676-684, 2017.

Electrophysiological and neuromuscular stability of persons with chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: We assessed motor unit (MU) properties and neuromuscular stability in the tibialis anterior (TA) of chronic inflammatory demyelinating polyneuropathy (CIDP) patients using decomposition-based quantitative electromyography. METHODS: Dorsiflexion strength was assessed, and surface and concentric needle electromyography were sampled from the TA. Estimates of MU numbers were derived using decomposition-based quantitative electromyography and spike-triggered averaging. Neuromuscular transmission stability was assessed from concentric needle-detected MU potentials. RESULTS: CIDP patients had 43% lower compound muscle action potential amplitude than controls, and despite near-maximum voluntary activation, were 37% weaker. CIDP had 27% fewer functioning MUs in the TA, and had 90% and 44% higher jiggle and jitter values, respectively compared with controls. CONCLUSIONS: CIDP had lower strength and compound muscle action potential values, moderately fewer numbers of MUs, and significant neuromuscular instability compared with controls. Thus, in addition to muscle atrophy, voluntary weakness is also due to limitations of peripheral neural transmission consistent with demyelination. Muscle Nerve 56: 413-420, 2017.

Reduced skeletal muscle quantity and quality in patients with diabetic polyneuropathy assessed by magnetic resonance imaging.

INTRODUCTION: The aim of this study was to determine whether diabetic polyneuropathy (DPN) is associated with reduced muscle quality using MRI. METHODS: MRIs of the tibialis anterior (TA) muscle were recorded from 9 individuals (5 men) with DPN (∼65 years) and 8 (4 men) age- and gender-matched controls. A magnetization transfer ratio (MTR) and T2 relaxation times of the TA were calculated. RESULTS: Despite equal voluntary activation, the DPN group was ∼37% weaker than controls, with a significantly lower proportion (∼8%) of contractile tissue and lower MTR (0.28 ± 0.03 vs. 0.32 ± 0.02 percent units). T2 relaxation time was significantly longer in the DPN group (77 ± 16 ms) compared with controls (63 ± 6 ms). CONCLUSIONS: These findings indicate a reduction in the structural integrity and myocellular protein density in the TA of those with DPN. Thus, muscle weakness in DPN is likely due to both a loss of muscle mass and a reduction in contractile quality.

Influence of needle electrode depth on DE-STA motor unit number estimation.

INTRODUCTION: To assess a potential source of technique-associated error, we evaluated the influence of needle electrode depth on decomposition-enhanced spike-triggered averaging (DE-STA) motor unit number estimation (MUNE) and quantitative motor unit analysis in the upper trapezius (UT). METHODS: The DE-STA MUNE protocol was performed at superficial, intermediate, and deep needle electrode depths in 18 control subjects. RESULTS: Mean surface-detected motor unit potential amplitudes were significantly smaller for intermediate versus superficial (P<0.05), deep versus superficial (P<0.001), and deep versus intermediate (P<0.05). MUNE was significantly larger for deep versus superficial (P<0.001), with statistical trends toward larger MUNE values at greater depths for the remaining comparisons. No significant differences were found among needle electrode depths for quantitative motor unit potential parameters. CONCLUSIONS: These results demonstrate the important influence of needle electrode depth on DE-STA MUNE in the UT. Suggestions are made for improved standardization of the protocol.

Anconeus motor unit number estimates using decomposition-based quantitative electromyography.

INTRODUCTION: Motor unit number estimates (MUNEs) provide important information in health, aging, and disease, and can be determined using decomposition-enhanced spike-triggered averaging (DE-STA). Discrimination of surface-detected motor unit potentials (S-MUPs) has been limited to contractile forces of ∽30% maximum voluntary contraction (MVC), which is insufficient to recruit a representative sample of the entire MU pool in most muscles. Unique features of the anconeus may permit MUNEs at high muscle activation levels. METHODS: In 10 men (25 ± 3 years), anconeus MUNEs were performed using DE-STA at 10%, 30%, and 50% root-mean-square of MVC (RMS(MVC)). RESULTS: The mean compound muscle action potential of the anconeus was ∽6 mV, and average S-MUP amplitudes were ∽100 µV, 145 µV, and 235 µV at 10%, 30%, and 50% RMS(MVC), resulting in low average MUNEs of 58, 38, and 25, respectively. CONCLUSIONS: Elbow extensor force-EMG relationships suggest full recruitment of the anconeus MU pool at 50% RMS(MVC), thus providing a representative sample for MUNE.

Motor unit number estimation: a technology and literature review.

INTRODUCTION: Numerous methods for motor unit number estimation (MUNE) have been developed. The objective of this article is to summarize and compare the major methods and the available data regarding their reproducibility, validity, application, refinement, and utility. METHODS: Using specified search criteria, a systematic review of the literature was performed. Reproducibility, normative data, application to specific diseases and conditions, technical refinements, and practicality were compiled into a comprehensive database and analyzed. RESULTS: The most commonly reported MUNE methods are the incremental, multiple-point stimulation, spike-triggered averaging, and statistical methods. All have established normative data sets and high reproducibility. MUNE provides quantitative assessments of motor neuron loss and has been applied successfully to the study of many clinical conditions, including amyotrophic lateral sclerosis and normal aging. CONCLUSIONS: MUNE is an important research technique in human subjects, providing important data regarding motor unit populations and motor unit loss over time.

Motor unit loss and weakness in association with diabetic neuropathy in humans.

INTRODUCTION: Diabetes mellitus can be associated with peripheral neuropathy which may affect numbers of functioning motor units (MUs) of limb muscles. Direct quantitative assessment of MU numbers and muscle strength have not been performed in humans. We compared the estimated number of MUs of individuals with diabetic polyneuropathy (DPN) versus controls. METHODS: Patients with signs/symptoms of DPN were studied using decomposition-enhanced quantitative electromyography of the tibialis anterior (TA). Motor unit number estimates were derived from this analysis. RESULTS: Dorsiflexion strength was ∼60% less in DPN than controls (P < 0.05). Additionally, the estimated number of functioning TA MUs was ∼60% fewer in patients with DM (∼46) versus controls (∼111) (P < 0.05). CONCLUSIONS: These data directly measure MU loss associated with DPN in a proximal muscle in humans. It remains to be determined whether quantifying MU loss has clinical utility in monitoring the progression or management of DPN.

Frailty and functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI): baseline results from the SYNERGIC Trial.

Functional brain connectivity (FBC), or areas that are anatomically separate but temporally synchronized in their activation, represent a sensitive biomarker for monitoring dementia progression. It is unclear whether frailty is associated with FBC in those at higher risk of progression to dementia (e.g., mild cognitive impairment -MCI-) and if sex plays a role. We used baseline data from the SYNERGIC trial, including participants with MCI that received brain MRI. In this cross-sectional analyses (n = 100), we measured frailty using a deficit accumulation frailty index. Using the CONN toolbox, we assessed FBC of networks and regions of interest across the entire connectome. We used Pearson's correlation to investigate the relationship between FBC and frailty index in the full sample and by sex. We also divided the full sample and each sex into tertiles based upon their frailty index score and then assessed between-tertile differences in FBC. The full sample (cluster: size = 291 p-FDR < 0.05) and males (cluster: size = 993 and 451 p-FDR < 0.01) demonstrated that increasing (stronger) connectivity between the right hippocampus and clusters in the temporal gyrus was positively correlated with increasing (worse) frailty. Males also demonstrated between-tertile differences in right hippocampus connectivity to clusters in the lateral occipital cortex (cluster: size = 289 p-FDR < 0.05). Regardless of frailty status, females demonstrated stronger within-network connectivity of the Default-Mode (p = 0.024). Our results suggest that increasing (worse) frailty was associated with increasing (stronger) connectivity between regions not typically linked, which may reflect a compensation tactic by the plastic brain. Furthermore, the relationship between the two variables appears to differ by sex. Our results may help elucidate why specific individuals progress to a dementia syndrome. NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676.

Combining exercise with cognitive training and vitamin D3 to improve functional brain connectivity (FBC) in older adults with mild cognitive impairment (MCI). Results from the SYNERGIC trial.

Changes in functional brain connectivity (FBC) may indicate how lifestyle modifications can prevent the progression to dementia; FBC identifies areas that are spatially separate but temporally synchronized in their activation and is altered in those with mild cognitive impairment (MCI), a prodromal state between healthy cognitive aging and dementia. Participants with MCI were randomly assigned to one of five study arms. Three times per week for 20-weeks, participants performed 30-min of (control) cognitive training, followed by 60-min of (control) physical exercise. Additionally, a vitamin D3 (10,000 IU/pill) or a placebo capsule was ingested three times per week for 20-weeks. Using the CONN toolbox, we measured FBC change (Post-Pre) across four statistical models that collapsed for and/or included some or all study arms. We conducted Pearson correlations between FBC change and changes in physical and cognitive functioning. Our sample included 120 participants (mean age: 73.89 ± 6.50). Compared to the pure control, physical exercise (model one; p-False Discovery Rate (FDR) < 0.01 & < 0.05) with cognitive training (model two; p-FDR = < 0.001), and all three interventions combined (model four; p-FDR = < 0.01) demonstrated an increase in FBC between regions of the Default-Mode Network (i.e., hippocampus and angular gyrus). After controlling for false discovery rate, there were no significant correlations between change in connectivity and change in cognitive or physical function. Physical exercise alone appears to be as efficacious as combined interventional strategies in altering FBC, but implications for behavioral outcomes remain unclear.

Decomposition-based quantitative electromyography in the evaluation of muscular dystrophy severity.

INTRODUCTION: Electromyography is useful in the diagnosis of myopathies, but its utility in determining disease severity requires further investigation. In this study we aimed to determine whether decomposition-based quantitative electromyography (DQEMG) could indicate the severity of involvement in a cohort of patients with muscular dystrophies (MDs). METHODS: Fifteen patients with facioscapulohumeral (FSHD), limb-girdle (LGMD), and Becker (BMD) muscular dystrophy, and 7 healthy controls, participated in this investigation. Knee extensor isometric strength differentiated the "more severe" and "less severe" MD groups. The vastus lateralis (VL), biceps brachii (BB), and tibialis anterior (TA) muscle groups were investigated using DQEMG. RESULTS: All muscles from the MD group showed changes in mean MUP (motor unit potential) AAR (area-to-amplitude ratio), and turns, compared with controls (P < 0.05). More severely affected muscles (VL and BB) also had shortened mean MUP durations compared with controls (P < 0.01). CONCLUSIONS: DQEMG was capable of indicating the severity of MD involvement, as changes in MUP morphology reflected the progressive nature of the disease.

Neck muscle responses evoked by transcranial magnetic stimulation of the human frontal eye fields.

Transcranial magnetic stimulation (TMS) provides a non-invasive means of investigating brain function. Whereas TMS of the human frontal eye fields (FEFs) does not induce saccades, electrical stimulation of the monkey FEF evokes eye-head gaze shifts, with neck muscle responses evoked at stimulation levels insufficient to evoke a saccade. These animal results motivated us to examine whether TMS of the FEF (TMS-FEF) in humans evokes a neck muscle response. Subjects performed memory-guided saccades to the left or right while TMS (two pulses at 20 Hz) was delivered on 30% of trials to the left FEF coincident with saccade instruction. As reported previously, TMS-FEF decreased contralateral saccade reaction times. We simultaneously recorded the activity of splenius capitis (SPL) (an ipsilateral head turner). TMS-FEF evoked a lateralized increase in the activity of the right SPL but not the left SPL, consistent with the recruitment of a contralateral head-turning synergy. In some subjects, the evoked neck muscle response was time-locked to stimulation, whereas in others the evoked response occurred around the time of the saccade. Importantly, evoked responses were greater when TMS was applied to the FEF engaged in contralateral saccade preparation, with even greater evoked responses preceding shorter latency saccades. These results provide new insights into both the nature of TMS and the human oculomotor system, demonstrating that TMS-FEF engages brainstem oculomotor circuits in a manner consistent with a general role in eye-head gaze orienting. Our results also suggest that pairing neck muscle recordings with TMS-FEF provides a novel way of assaying the covert preparation of oculomotor plans.

Vastus medialis motor unit properties in knee osteoarthritis.

BACKGROUND: Maximal isometric quadriceps strength deficits have been widely reported in studies of knee osteoarthritis (OA), however little is known about the effect of osteoarthritis knee pain on submaximal quadriceps neuromuscular function. The purpose of this study was to measure vastus medialis motor unit (MU) properties in participants with knee OA, during submaximal isometric contractions. METHODS: Vastus medialis motor unit potential (MUP) parameters were assessed in 8 patients with knee OA and 8 healthy, sex and age-matched controls during submaximal isometric contractions (20% of maximum isometric torque). Unpaired t-tests were used to compare groups for demographic and muscle parameters. RESULTS: Maximum knee extension torque was ~22% lower in the OA group, a difference that was not statistically significantly (p = 0.11). During submaximal contractions, size related parameters of the needle MUPs (e.g. negative peak duration and amplitude-to-area ratio) were greater in the OA group (p < 0.05), with a rightward shift in the frequency distribution of surface MUP negative peak amplitude. MUP firing rates were significantly lower in the OA group (p < 0.05). CONCLUSIONS: Changes in MU recruitment and rate coding strategies in OA may reflect a chronic reinnervation process or a compensatory strategy in the presence of chronic knee pain associated with OA.

Length-dependent changes of lower limb muscle morphology in Chronic Inflammatory Demyelinating Polyneuropathy assessed with magnetic resonance imaging.

The objective of the present study was to assess muscle quantity of the thigh and leg in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) compared to age and sex matched controls in exploring length-dependent changes of innervated muscles. In five people with CIDP and seven controls, magnetic resonance imaging was used to assess muscle morphology of the four parts of the quadriceps and medial hamstring muscles. Findings were compared to the triceps surae from a subset of participants. The CIDP group had less contractile tissue in the quadriceps (11.5%, P<0.05), hamstrings (15.6%, P<0.05) and triceps surae (35.9%, P<0.05) compared to controls. Additionally, CIDP had less contractile tissue (18.7%) in the triceps surae compared to the hamstrings (P<0.05). Muscle quantity in the quadriceps and hamstrings in CIDP was less than controls, but differences were greater for the distal triceps surae. These findings support a length-dependent affect of CIDP on limb musculature composition.