Muscle & Nerve

Spinal cord injury (SCI) is a devastating neurological injury that results in the profound loss of voluntary motor function and marked reduction in quality of life. Rehabilitation remains as the standard of care for recovery after SCI; however, it often falls short in recovering meaningful motor function. Spinal cord stimulation (SCS) has emerged as a promising neurostimulation approach to fill this gap and recover lost voluntary motor function. Two main approaches of SCS have been designed and implemented for human use: epidural and transcutaneous SCS. Over the last two decades, several clinical studies have shown convincing evidence that both epidural and transcutaneous SCS can be used in conjunction with rehabilitation to improve motor function of individuals after SCI. Yet fundamental clinical questions remain unanswered: when should clinicians choose epidural or transcutaneous SCS, which technique provides the most durable outcomes, and for whom is each therapy best? Without these answers, widespread and meaningful adoption of either approach into clinical practice will remain limited. To address these questions, in this Review, we define the distinct therapeutic goals, intended use cases, clinical parameters, and responder profiles for both epidural and transcutaneous SCS to guide their eventual adoption into clinical practice. We found that indeed epidural and transcutaneous SCS serve distinct therapeutic roles. Epidural SCS is designed as an assistive therapy that can restore muscle activity and single joint movements immediately within one week of implantation, while transcutaneous SCS is designed as a long-term therapeutic device with cumulative functional gains observed over treatment periods of up to 18 weeks. Lastly, epidural SCS produced benefits for all participants (AIS A-D) despite the extent of their injury, while transcutaneous SCS only consistently benefits individuals with incomplete motor injuries (AIS C-D).

Background: Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene and represents the most common adult-onset myopathy. Current molecular diagnostics rely on labor-intensive assays that limit accessibility and scalability. Haplotype-based approaches offer a promising alternative for detecting pathogenic expansions indirectly. Methods: We performed genome-wide genotyping in 226 genetically confirmed DM1 patients from the Saguenay-Lac-Saint-Jean founder population and reconstructed haplotypes surrounding the DMPK pathogenic repeat expansion. Based on these haplotypes, we performed a phylogenetic analysis that was further integrated with genealogical reconstruction from the BALSAC database to investigate the origin and transmission of DM1 haplotypes. To evaluate epidemiological utility, we implemented gene dropping simulations within the SLSJ extended genealogies (>80,000 starting individuals) to estimate DM1 incidence at birth. Results: A DM1-associated haplotype was identified in all patients (226/226), consistent with a single major ancestral origin in the SLSJ population. This complete concordance supports the robustness of haplotype-based approaches to infer carrier status without direct repeat sizing. Integrating phylogenetic analysis and genealogical data identified a single couple as the most likely entry point of DM1 in Quebec. Simulation-based estimates of incidence at birth exceeded observed prevalence, suggesting underdiagnosis in the region. Marked geographic heterogeneity in the SLSJ is also observed. Conclusions: Our results demonstrate that haplotype-based approaches can provide a reliable, cost-effective alternative to conventional pathogenic DM1 repeat carriers identification and familial screening strategies.

Objectives: To develop and validate a disease-specific patient-reported outcome (PRO) measure for spinal and bulbar muscular atrophy (SBMA). Methods: A three-stage sequential design was adopted. Items were generated through qualitative interviews with patients with SBMA and expert review, refined using quantitative analyses, and evaluated for reliability and validity in independent cohorts from Japan and the United States. Results: Interviews with 12 patients generated 234 candidate items, which were refined into a final 31-item SBMAPRO comprising five domains based on an online survey of 106 patients. Internal consistency across domains ranged from Cronbach's alpha values of 0.651 to 0.901. In the Japanese cohort, test-retest reliability yielded intraclass correlation coefficients of 0.941 for physical function, 0.877 for mental health, and 0.858 for social function. Construct validity was examined through correlations with disease-specific functional measurements and the 36-Item Short Form Survey (SF-36). The SBMAPRO correlated with the SBMA Functional Rating Scale (r = -0.826, p <0.001) and with the SF-36 mental health (r = -0.693, p <0.001) and social functioning (r = -0.617, p <0.001) domains. In subscale analyses, the SBMAPRO social domain was associated with trunk-lower limb-related functional impairment (r = -0.587, p < 0.001). Similar patterns were observed in the American cohort. Conclusion: The SBMAPRO demonstrated reliability and validity in Japanese and American cohorts. Associations between mental and social domains and trunk-lower limb dysfunction suggest that mobility impairment may contribute to psychological burden and restricted social participation in SBMA, indicating that this disease-specific PRO may complement clinician-rated measures.

Purpose: Pathogenic variants in NFIX cause Marshall-Smith syndrome and Malan syndrome (MALNS). We identified a severe subtype of MALNS characterized by adolescent-onset musculoskeletal deterioration and investigated functional consequences of underlying variants. Methods: Clinical data were collected from seven individuals with pathogenic NFIX variants. Wild-type and mutated recombinant NFIX DNA-binding domains (DBDs) were evaluated using biochemical, structural, and DNA-binding assays. Results: Six individuals carrying R116W, R116P, K125E, or G147E NFIX substitutions developed progressive muscle wasting, markedly reduced body mass index, and rapidly progressive scoliosis after the typical childhood features of MALNS; two died from disease-related complications. A seventh individual with R116G did not develop this severe phenotype. Functional studies on recombinant NFIX DBDs showed complete or near-complete loss of DNA-binding activity for R116W, R116P, K125E, and G147E despite preserved protein folding, consistent with disrupted DNA recognition and a potential dominant-negative mechanism. In contrast, R116G exhibited a 7.7{degrees}C decrease in thermal stability, which may support haploinsufficiency mediated by protein degradation. Conclusion: Specific NFIX missense variants define a severe subtype of MALNS associated with progressive musculoskeletal deterioration. In vitro functional studies support variant-specific disruption of DNA binding, providing a mechanistic basis of genotype-phenotype correlations and informing prognosis, clinical surveillance, and therapy development.

Background: Gait impairment is common among people with multiple sclerosis (PwMS) and is an important marker of disease progression. However, gait assessments typically require in-person evaluations. Objective: To describe the pose-estimation-based method for estimating spatiotemporal gait parameters from a single consumer-grade video, and evaluate the feasibility of home video collection by PwMS. Methods: In a single-center longitudinal digital phenotyping study, ambulatory adults with MS completed a standardized walking task recorded in the frontal plane. Pose estimation (MediaPipe Pose, Ultralytics) and custom scripts were used to estimate gait parameters from videos. Participants were invited to record walking videos at home using personal devices. Adoption and technical feasibility were evaluated across two home video data acquisition phases, with iterative protocol refinements. Results: The in-clinic study included 132 participants; 55 contributed home videos. In Phase I, while home video adoption was low (45% [30/66]), 87% [26/30] uploaded [&ge;]1 video of sufficient quality for gait analysis. After protocol refinements, 100% [25/25] uploaded [&ge;]1 high-quality video. Overall, high-quality frontal-plane videos were obtained at similar rates at home (92% [97/105]) and in-clinic (91% [423/467]). Conclusions: Home walking videos can feasibly be collected by PwMS to estimate gait parameters, providing an accessible approach for remote gait monitoring.

Motor speech disorders (MSDs) are early markers of neurological disease, but expert perceptual analysis is rarely available outside specialized centers. Automated speech analysis offers a scalable alternative, yet prior studies have not systematically compared modeling approaches or assessed clinically relevant metrics in independent datasets. This study compared static acoustic features, articulatory informed Phonet features, and self-supervised pretrained models for binary and multi label MSD classification. We trained and evaluated models on 583 speech samples using speaker level splits. Baseline models included logistic regression and Gated Recurrent Units (GRUs) trained on eGeMAPS and MFCCs. We extracted three types of Phonet derived features and evaluated pretrained HuBERT and SSAST models in frozen, partially fine-tuned, and fully fine-tuned configurations. Binary classification distinguished MSDs from controls, while multi label classification identified six MSD subtypes. Models were assessed using validation AUC, and cut points were tested on two independent datasets. Pretrained and Phonet based models substantially outperformed static acoustic features. In binary classification, HuBERT achieved the highest AUC (0.95), while compact Phonet derived GRUs achieved comparable performance (up to 0.94). These models generalized well to independent datasets, maintaining high sensitivity (0.94) and specificity (0.97). In multi label classification, Phonet models achieved the highest macro average AUC (0.86), but threshold-based subtype performance declined on unseen data. Automated MSD detection is feasible and clinically promising. Binary classification generalized well, whereas multi label classification showed limited threshold stability across datasets.

Myotonic Dystrophy type 1 (DM1) is an autosomal multisystem disorder manifested due to unstable CTG nucleotide repeat expansion within the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Although progress towards understanding of molecular pathogenesis in muscle and heart has been made, the pathways that affect the brain in DM1 is fundamentally unknown. In addition, the congenital DM1 manifest even more complicated brain abnormalities. Despite the wealth of existing cellular and animal models, iPSCs based studies are being fostered as they replicate the human model more closely to the disease. In view of this context, we set out to characterize the differentiation potential of congenital DM1 patient derived iPSC lines towards neuronal cells. Using neurogenin2 (NGN2) induced direct reprogramming of iPSCs into neurons and chemically defined media-induced neural induction protocol, we find that congenital DM1 mutant iPSC derived neurons exhibited precocious differentiation, as evidenced by their expression of pan-neuronal markers TUJ1 and Map2, along with increased processes extension and neurite length. Moreover, unbiased RNA sequencing analyses and qPCR validation revealed precocious and enhanced expression of several neurogenic transcription factors including, Ascl1, NeuroG2, and NeuroD1. Furthermore, immunofluorescence imaging of MBNL1 and MBNL2, RNA-splicing factors, displayed enhanced nuclear aggregations, a hallmark of the DM1 disease, in the mutant lines. Moreover, investigation of RNA splicing events identified mis-splicing in many important genes/transcripts including RMST, ANK3 and MBD1 during the neural conversion of congenital DM1 lines. These studies reveal novel paradigms that may contribute to neurological pathogenesis in CDM1 patients. These studies also provide a strong foundation for future mechanistic investigation aimed at understanding CDM1 pathology and may open new avenues for the development of gene therapy approaches for individuals with DM1.

Laminin-2 (gene: LAMA2) is a key protein in the basement membrane of muscle and Schwann cells. A complete lack of this protein results in LAMA2-related congenital muscular dystrophy (LAMA2-RD), a severe muscle disease characterized by progressive muscle weakness, respiratory insufficiency, failure to thrive and shortened life span. One key signature of this disease is early onset of fibrosis coupled with poor muscle growth. We previously showed that TGF-{beta} and its activator, integrin-V, are elevated in dystrophic fibers of DyW mice, a mouse model of LAMA2- RD. Other than activating TGF-{beta}, integrin-V is also known to facilitate the transdifferentiation of various cell types to myofibroblasts. In this study we present evidence for transcriptional dysregulation of genes driving myofibroblast transdifferentiation and extracellular matrix (ECM) remodelling during the early development of DyW mice that is also reflected in muscle biopsies from young LAMA2-RD patients. We hypothesize that the early ECM remodelling, seen in both DyW mice and LAMA2-RD children, may explain the congenital onset of fibrosis with poor muscle growth seen in the disease.

Background: Neurofilament light chain (NfL) gained FDA recognition in amyotrophic lateral sclerosis (ALS) through SIMOA-based validation, where baseline serum NfL predicts ALSFRS-R slope and survival, and through the 2023 tofersen approval for SOD1-ALS. The commercial Roche Elecsys electrochemiluminescence immunoassay (ECLIA) reads 6- to 8-fold lower than SIMOA, and its clinical utility in ALS is uncharacterized. We assessed whether ECLIA NfL retains this correlation in routine care and whether GFAP or S-100B helps. Methods: Retrospective analysis of 58 chart-confirmed ALS patients at Georgetown University Hospital (2022-2026), biomarkers on the LabCorp Roche Elecsys ECLIA. The NfL-ALSFRS-R correlation was assessed where both measures fell within matching windows; serial NfL, in patients with repeat draws. Results: First-per-patient NfL median was 7.06 pg/mL (IQR 4.06-17.30; CV 99%). Among 31 patients with matched NfL and ALSFRS-R decline rates, Spearman r = 0.704; within 90 days (n = 17), r = 0.809 (both p < 0.0001). Fast progressors (n = 8) had mean NfL 17.10 pg/mL versus 4.64 in slow progressors (n = 21), a 3.7-fold separation. Serial NfL captured rising trajectories and stable low values. GFAP rose within patients but tracked neither progression rate, disease stage, nor motor-neuron predominance; S-100B added no value. Conclusions: Commercial ECLIA brings NfL into routine ALS care; its prognostic correlation with progression rate survives real-world fragmentation. The actionable unit is the longitudinal trajectory, not the single value, read against platform-specific reference ranges and clinical context (genotype, onset, stage). GFAP and S-100B add little. Keywords: amyotrophic lateral sclerosis, neurofilament light chain, biomarkers, implementation science, ECLIA, GFAP, monitoring, tofersen, real-world data

A major obstacle for clinical trials is the lack of objective, sensitive, and reliable measures that can detect modest changes in disease progression. Here, we determine whether acoustic and linguistic digital speech measures automatically obtained during a functionally relevant passage-reading task capture multiple dimensions of disease in ataxia, including functional communication impairment, subclinical cerebellar dysfunction and disease progression. A total of 157 individuals with ataxia and 84 controls contributed cross-sectional data, and 54 individuals with ataxia and 43 controls contributed longitudinal data within the ongoing Neurobooth natural history study. Participants completed standardized speech recordings, patient-reported outcome measures (PROMs) and neurologist-rated clinical evaluations. A novel speech processing pipeline was developed to automatically transcribe audio recordings, identify word boundaries and extract a predefined set of linguistic and within-word acoustic features. Individuals with ataxia exhibited marked disruption of speech timing, coordination and articulatory control, including slowed speech (d=1.23), prolonged inter-word pauses (d=-0.91), higher/more variable vocal intensity (|d|=0.43-0.51) and altered spectral content (|d|=0.43-0.79) compared to healthy controls. Linguistic features (e.g. speaking rate and within-word pause duration) showed strong associations with clinician-rated severity and PROMs (|r|=0.23-68), indicating alignment with functional communication impairment and patient-perceived disease burden. In contrast, acoustic features derived from cepstral measures captured subtle abnormalities in speech motor control, differentiating not only individuals with ataxia (d=0.65) but also pre-ataxic individuals (d=0.56), and those without clinically evident dysarthria (d=0.45), from controls. These findings indicate that acoustic features reflect subclinical cerebellar motor dysfunction involving impaired temporal coordination and vocal control before overt clinical speech impairment emerges. Longitudinally, several acoustic measures were sensitive to disease progression (MSDR=0.19-0.68), even in cases where clinical scales showed no detectable change. Speech-derived changes correlated with changes in clinical scales and PROMs. Both acoustic and linguistic features exhibited strong intra-session reliability. During passage reading, acoustic and linguistic measures provide complementary but different clinical information in ataxias. Linguistic measures primarily reflect downstream functional consequences of ataxic dysarthria, whereas acoustic measures provide sensitive indicators of subclinical cerebellar motor dysfunction and progression. These findings demonstrate that natural speech analysis can produce digital measures for detecting subclinical disease, quantifying functional impairment, monitoring progression in ataxia, with strong potential for application in clinical trials and remote monitoring.

Background and Objectives To investigate the associations of blood-based tau biomarkers with clinical, electrophysiologic and prognostic measures in amyotrophic lateral sclerosis (ALS), and to determine whether they reflect distinct disease-related processes. Methods We studied 119 patients with ALS from a longitudinal observational cohort. Plasma and serum p-tau181, p-tau217, p-tau231, brain-derived tau (BD-tau), NfL and GFAP were measured using Lumipulse and Simoa assays. Associations with demographic variables, disease severity (ALSFRS-R and slow vital capacity), lower motor neuron (LMN), muscle involvement (creatine kinase [CK] and high-sensitivity cardiac troponin T [hs-cTnT]), disease progression and survival were assessed using multivariable models. Results Tau-related biomarkers, specifically p-tau217 and BD-tau, were associated with greater cross-sectional disease severity, reflected by lower ALSFRS-R scores. Plasma and serum p-tau181, p-tau217, p-tau231, and BD-tau were associated with higher CK and hs-cTnT, whereas p-tau181 and p-tau231 were also associated with greater LMN involvement. In contrast, NfL and GFAP were not associated with muscle or LMN involvement. Across analytical platforms, plasma and serum NfL were associated with faster ALSFRS-R decline and shorter survival. NfL was the only biomarker independently associated with both disease progression and survival. Discussion Blood biomarkers capture distinct dimensions of ALS. Tau-related biomarkers are associated with cross-sectional disease severity, LMN involvement and muscle injury, whereas NfL primarily reflects disease progression and survival. These findings support the complementary use of tau-related biomarkers and NfL for ALS phenotypic characterization and prognosis assessment.

Background Cortical processing of the knee-joint proprioception is largely unknown. Magnetoencephalography (MEG) can be used to quantify the cortical processing of the proprioceptive afference, but MEG-compatible and well-controlled stimulation of the knee joint is technically challenging, and thus has received less attention. New method We introduced a novel MEG-compatible stimulator that delivers controlled patellar tendon stretches to activate muscle afferent of the knee extensors. The stimulus intensity is adjustable, allowing graded activation of proprioceptive input and, when required, elicitation of the patellar-tendon reflex. Results The novel stimulator elicited clear muscular and cortical responses in both intensity conditions. Cortical responses demonstrated moderate to excellent intersession reliability for peak evoked field amplitude (ICC: 0.69--0.96), beta suppression (0.89--0.90) and beta rebound (0.96--0.97). Notably, beta suppression peaked more laterally than expected in both hemispheres. Peak EMG amplitudes in VL and VM muscles were reliable for both intensity conditions (ICC: 0.66--0.89), and stimulus kinematics remained consistent throughout measurements. Comparison with existing methods Previous robotic or motor-driven devices have been used to evoke cortical responses to knee-joint proprioceptive stimulation, but mechanical coupling across adjacent joints may limit knee-specific input. The present stimulator provides mechanically simple and MEG-compatible alternative that targets knee extensor afferents more directly, reduces distal joint involvement. Conclusion The novel stimulator is a feasible and repeatable tool to study cortical processing of proprioceptive afference from the knee-joint using MEG. The spatially unexpected beta rhythm suppression suggests that knee-joint proprioceptive afference may involve more unique sensorimotor cortical neuronal network than previously recognized.

Resistance training lasting a few weeks increases maximal force mainly through neural adaptations that enhance the drive from the nervous system to muscle. While these adaptations have been well documented at the motor unit (MU) level during submaximal force contractions, the mechanisms underlying force increases during maximal voluntary contractions are poorly understood. This is due to a classic technical limitation in tracking MUs longitudinally during maximal force tasks. Here, we solved this technical challenge, enabling the investigation of MU adaptations during MVCs in both the trained and untrained limbs following unilateral resistance training. High-density surface electromyography was recorded from the biceps brachii of both limbs before and after a 4-week unilateral resistance-training intervention, and the same MUs were longitudinally tracked across sessions during MVCs by concatenation of three MVC trials of ~5-s each.Unilateral training increased maximal force in the trained limb (+16%) and induced strength transfer to the untrained limb (+8%). In both limbs, maximal contractions after training were characterized by greater EMG amplitude, faster muscle-fiber conduction velocity, and higher MU discharge rates, indicating enhanced neural drive to the motoneuron pool. These adaptations were strongly associated with improvements in maximal force (R2 > 0.7 for all). Importantly, longitudinal MU tracking revealed a non-uniform adaptation across the MU pool: MUs with higher baseline conduction velocity, indicative of higher recruitment threshold, exhibited the largest pre-post increases in discharge rate, whereas lower-threshold units showed smaller changes. Collectively, these findings demonstrate that gains in maximal force and their transfer to the untrained limb are primarily mediated by enhanced rate coding of higher-threshold MUs during MVCs.

IntroductionThe quality of preclinical studies for rare diseases, such as Duchenne muscular dystrophy (DMD), relies on the availability of comprehensive natural disease history data. In addition to the classic BL10-mdx mouse, in recent years, the D2-mdx model has increasingly been used as an alternative model due to its reportedly more severely impaired phenotype. To improve our understanding of disease progression in these two DMD models, we conducted a comprehensive natural history study. Materials and MethodsThis involved a cross-sectional analysis of key in vivo and ex vivo outcome measures performed in two independent laboratories, using the same study setup in compliance with TREAT-NMD Standard Operating Procedures (SOPs), while also taking advantage of site-specific expertise. Globally, largely comparable results were obtained across the two study sites. ResultsBody composition showed pronounced differences between the strains, with BL10-mdx mice displaying a hypertrophic and D2-mdx mice displaying an atrophic phenotype. Dystrophic mice of each strain exhibited significant alterations of disease-relevant indices related to muscle functionality and integrity, mostly worsening with age, in comparison to their wildtypes. Cardiac function was affected earlier and more severely in D2-mdx mice. DiscussionNotably, for some parameters, genetic-background related differences were observed, emphasizing the need to include control groups with matching genetic backgrounds in experimental designs. ConclusionsCollectively, our natural history study provides benchmark data for these two mdx mouse strains to guide model selection for preclinical DMD studies, allowing accurate data interpretation. HighlightsO_LIDistinct body composition phenotypes: BL10-mdx mice exhibit pseudohypertrophy while D2-mdx mice display pronounced atrophy. C_LIO_LIEarlier cardiac dysfunction in D2-mdx: D2-mdx mice develop reduced ejection fraction and stroke volume from 28 weeks, while BL10-mdx only at 52 weeks. C_LIO_LIGenetic background-dependent variations: Intrinsic deficits in wildtype D2 mice demonstrate that genetic background influences outcome measures independent of dystrophic pathology. C_LIO_LIComparable ex vivo muscle physiology: Despite divergent in vivo phenotypes, isolated muscle contractile parameters show similar impairment in both dystrophic models. C_LIO_LIMulti-site standardized validation: Cross-sectional study at two independent laboratories following harmonized TREAT-NMD Standard Operating Procedures. C_LI

Neural stem cell (NSC) transplantation is a promising strategy for repairing the injured spinal cord, but transplanted cells typically require immunosuppressive therapy to prevent rejection, even for induced pluripotent stem cell (iPSC)-derived autologous grafts. However, the effects of immunosuppressive drugs on neurite outgrowth and axonal regeneration, processes critical for neural circuit reconstruction, have not been fully characterized. In this study, we tested nine clinically relevant immunosuppressants on human iPSC-derived neurons and primary human spinal cord NSCs in vitro at concentrations approximating clinical exposure levels. The drug panel included FK-506 (tacrolimus), cyclosporine A (CsA), rapamycin, belatacept (Nulojix), etanercept (Enbrel), mycophenolate mofetil (CellCept), cyclophosphamide (Cytoxan), prednisone, and azathioprine (Imuran). Neurite outgrowth was quantified via automated high-content imaging. Multiple agents, including CsA, Imuran, Nulojix, and CellCept, induced significant reductions in neurite outgrowth in a cell type- and dose-dependent manner, with CsA producing the most robust and consistent inhibition across both cell lines. In contrast, FK-506 showed no significant effect on neurite extension at clinically relevant concentrations. Consistent with the in vitro results, human neural progenitor cell grafts in a rodent spinal cord injury model exhibited significantly reduced graft-derived axon extension in the host spinal cord when hosts were treated with CsA rather than FK-506. These findings demonstrate that immunosuppressant choice can profoundly influence neural graft integration and axonal regeneration. Our study underscores the importance of preclinical evaluation of immunosuppressive regimens and suggests that selecting agents such as FK-506 over CsA may improve outcomes in future stem cell-based therapeutic trials for spinal cord injury and related disorders of the central nervous system.

Peripheral nerve injuries often result in prolonged skeletal muscle denervation, leading to progressive atrophy, fibrosis, neuromuscular instability, and loss of regenerative capacity before axons can reinnervate distal targets. Here, we developed a non-viral strategy using tissue nanotransfection (TNT) to deliver the neurogenic transcription factor cocktail Ascl1, Brn2, and Myt1l (ABM) directly to denervated skeletal muscle. In vitro, ABM-transfected myoblasts sustained expression of the reprogramming factors, acquired neuron-like morphologies, upregulated neuronal markers including Tuj1, Map2, and Syp, and exhibited electrophysiological properties consistent with membrane excitability. RNA sequencing confirmed broad activation of neurogenic transcriptional programs, with enrichment of pathways associated with neuronal fate commitment, neuron differentiation, axon guidance, synaptogenesis, and developmental signaling. In a mouse model of sciatic nerve transection, TNT enabled localized ABM expression in denervated gastrocnemius muscle. ABM-TNT treatment accelerated resolution of denervation-associated fibrillation potentials and showed trends toward improved twitch and tetanic torque, compound muscle action potential amplitudes, and muscle mass preservation. Transcriptomic profiling of treated muscles 5 weeks after injury revealed distinct gene expression programs enriched for muscle regeneration, neuromuscular organization, trophic support, extracellular matrix remodeling, angiogenesis, myogenesis, and metabolic adaptation. Network analyses further identified activation of neurogenic regulators, neurotrophic signaling, and vascular-support pathways. These findings establish TNT-mediated ABM delivery as a non-viral platform for inducing neurogenic and myoprotective programs in denervated muscle, suggesting a potential strategy to preserve muscle viability during the prolonged interval required for peripheral nerve regeneration.

Skeletal muscles secrete a variety of cytokines in response to inflammatory stimuli such as lipopolysaccharide (LPS); however, the contributions of resident macrophages or other non-muscle cells to the secretory responses are not well understood. To determine the potential impact of resident macrophages to inflammatory cytokine production, we tested the LPS responsiveness of isolated mouse soleus muscle when a critical toll receptor adapter protein (Myd88) was knocked down only in myeloid-derived cells within the muscle (e.g. resident macrophages). The phenotype is referred to as LyzMyd88-/- ; the litter mate controls were Myd88fl/fl. In solei from LyzMyd88-/- mice, cytokine secretory rates for interleukin-6 (IL-6) and keratinocyte-derived cytokine (KC, CXCL1) were significantly reduced to 56.3%, and 60.6% of control, respectively, over the first hour of LPS exposure. In the second hour, secretion of granulocyte colony stimulating factor (G-CSF), IL-6, KC(CXCL1) and monocyte chemoattractant protein-1 (MCP-1, CCL2) were greatly elevated by 5-10-fold in both phenotypes compared to the first hour. However, only MCP-1 secretion was decreased to 70.6% of control in the second hour. We also tested the secretory response to buffer containing 1% sterile mouse plasma because dilute plasma is known to amplify the responses of macrophages to LPS. Treatment with 1% plasma alone affected baseline measures of some cytokines but resulted in no further increases in secretion during either hour of exposure. However, small and gradual increases in secretory rates were observed for several cytokines over the study period, with or without plasma, with the largest responses seen in IL-6 and KC. Overall, the results are consistent with a significant early contribution of myeloid-derived, resident immune cells to the cytokine secretory responses of intact oxidative skeletal muscle. In addition, small quantities of plasma in the buffer have no independent stimulatory effects on cytokine secretion

Purpose: The purpose of this study was to identify subgroups of talkers with Parkinsons disease (PD) with shared tongue, lip, and jaw articulatory amplitude behaviors. The study also sought to identify demographic and clinical features that can distinguish the identified kinematic subgroups. Methods: 53 talkers with PD and 54 controls participated. Articulatory amplitudes of the tongue, lip, and jaw were measured during a paragraph reading task using three-dimensional electromagnetic articulography. Amplitude performance profiles of the tongue, lip, and jaw were established for each talker with PD by referencing their performance to that of controls. These profiles were submitted to a hierarchical cluster analysis to identify kinematic-based subgroups. Amplitude performances were compared across subgroups to determine between-group patterns. Demographic and clinical features (e.g., age, sex, disease duration, selected perceptual speech characteristics, dysarthria severity) were compared across the identified kinematic subgroups. Results: Four main kinematic subgroups with differing amplitude performance profiles were identified. One subgroup exhibited normal to mildly exaggerated or mildly reduced amplitudes and was labeled preclinical subgroup (n = 16). Three subgroups exhibited pronounced amplitude reductions of either the tongue (n = 10), the tongue and lips (n = 12), or the tongue, lips, and jaw (n = 10). In addition, there were five talkers with PD whose performance profiles did not align with the identified four subgroups. Their performance was characterized by either pronounced amplitude exaggerations or mildly reduced jaw and lip amplitudes and exaggerated tongue amplitudes. None of the demographic or clinical features differed significantly between the main four subgroups. Conclusion: Findings suggest that the extent to which hypokinesia manifests within the articulatory subsystem can vary in talkers with PD. Longitudinal studies are needed to determine if these subgroups represent different stages of disease progression or distinctly different manifestations of the disease within the articulatory subsystem.

This study examined the extent to which goodness of pronunciation (GoP) scores and phonological posterior probabilities capture perceptual ratings of speech severity in individuals with motor speech disorders (MSD). Speech recordings of the word catastrophe were obtained from 489 participants, including 333 neurologically typical controls and 156 individuals with MSD. GoP scores were derived using traditional acoustic features and self-supervised speech representations, including WavLM and XLS-R, across multiple modeling approaches, while phonological posterior probabilities were extracted using Phonet. Model performance was evaluated using Kendall's rank correlations, regression, and receiver operating characteristic analyses against speech-language pathologists' perceptual ratings of sound distortion and intelligibility. Both GoP and phonological posterior probabilities were significantly associated with perceptual ratings. Self-supervised speech representations substantially outperformed traditional acoustic features, with WavLM-based GoP using k-nearest neighbors achieving the strongest performance. Across correlation, regression, and classification analyses, GoP consistently outperformed phonological posterior probabilities for both sound distortion and intelligibility. Age and gender had minimal influence on model-derived measures or their relationships with perceptual ratings. These findings demonstrate the value of self-supervised GoP as an objective measure of speech impairment while highlighting the complementary role of phonological posterior probabilities in characterizing articulatory aspects of motor speech disorders.

Neuromuscular contractures arising from neonatal brachial plexus injuries (NBPI) are highly disabling and currently incurable. We previously showed that contractures involve impaired longitudinal growth of denervated muscles, a defect mediated through myostatin (MSTN) signaling, a potent negative regulator of muscle size. However, MSTN-mediated contractures occur independent of canonical signaling pathways, including SMAD 2/3 and AKT/mTOR. Through a mouse model of NBPI, our present study extended these findings by revealing pharmacologic inhibition of JNK signaling, a noncanonical pathway downstream of MSTN, partially rescues contractures without restoring muscle length. Rather, JNK activation upregulates myofiber expression of the target gene Lmna, which encodes the nuclear envelope proteins Lamin A and Lamin C that are vital for nuclear stability, resulting in pervasive myonuclear displacement. These results suggest that other factors contribute to contracture pathology beyond deficits in longitudinal muscle growth. Further, while JNK inhibition does not restore length of denervated muscles, it impedes size and mass of normally innervated neonatal muscles, suggesting a requirement of JNK signaling for neonatal muscle growth. Our collective findings thereby establish new mechanistic insights into the molecular basis of aberrant muscle growth and neuromuscular contracture formation, potentially leading to novel targets for muscle restorative strategies and medical contracture prevention.