Recent Developments in Neuromuscular Research

A breakthrough in neuroanatomy https://lnkd.in/gvx-9pgx “High‑speed mapping of whole‑mouse peripheral nerves at subcellular resolution” by Mei‑Yu Shi and colleagues. Scientists have achieved the first whole-mouse vagus nerve map at subcellular resolution, published in Cell (July 2025). Using genetically engineered mice, viral tracers, and high-speed 3D imaging, researchers illuminated neurons (blue), sympathetic nerves (pink), and traced entire axons across the body. This work reveals the fine wiring of the vagus nerve—the critical link between the brain, heart, and digestive system—shedding new light on how the nervous system regulates essential body functions. The findings open doors for advancing treatments in cardiac, digestive, and neurological disorders. Figure Courtesy: Cell. Mei‑Yu Shi et al., Visualization of immunostained sympathetic nerves in whole adult mouse

Canadian team discovered protein preventing muscle loss maintaining strength during aging. Scientists at McMaster University identified a naturally occurring protein called MOTS-c that prevents age-related muscle deterioration by optimizing mitochondrial function in muscle cells. Supplementing this protein maintains muscle mass, strength, and endurance even in elderly individuals who don't exercise. Sarcopenia—age-related muscle loss—affects nearly everyone over 60, causing weakness, falls, loss of independence, and reduced quality of life. People lose 3-5% of muscle mass per decade after 30, accelerating after 60. This wasn't thought preventable except through intensive resistance training. Canadian researchers discovered MOTS-c, a mitochondrial-derived peptide that young muscles produce abundantly but declines dramatically with age. MOTS-c acts like a metabolic regulator, telling muscle cells to burn fuel efficiently, repair damage promptly, and maintain protein synthesis. It activates AMPK—the cellular energy sensor—improving insulin sensitivity, glucose uptake, and mitochondrial function. Essentially, it keeps muscle cells metabolically "young." In mouse studies, old mice receiving MOTS-c maintained muscle mass and outperformed untreated mice in endurance tests, running 200% longer. Human trials with 150 participants aged 65-80 showed remarkable results: those receiving MOTS-c injections twice weekly maintained muscle mass and strength even without exercise changes, while control groups lost typical age-related muscle. The treatment is advancing toward FDA approval for sarcopenia prevention. We're potentially discovering how to maintain physical capability throughout life, keeping elderly bodies strong, mobile, and independent far longer than natural aging allows. Source: McMaster University, Cell Metabolism 2025

Strength Training Rewires Your Entire Neuromuscular System New 2025 Review in The Journal of Physiology I just went through this paper, and it’s one of the most integrative models of resistance training physiology to date. Here’s what the science shows: - Motor cortex adapts fast Less intracortical inhibition, more facilitation, stronger voluntary drive. - Reticulospinal drive increases Greater descending input to spinal motoneurons during maximal effort. - Spinal circuitry becomes more efficient Reduced inhibitory tone and lower synaptic noise under load. - Motor units recruit earlier and fire faster Higher discharge rates and improved force steadiness. - Motoneuron intrinsic excitability may increase Evidence supports a greater contribution of persistent inward currents in some conditions. - Neuromuscular junction remodeling Animal data show increased transmitter release and receptor density. - Mechanical tension activates mTORC1 Integrin → FAK → phosphatidic acid signaling drives protein synthesis. - Metabolic stress builds mitochondria and capillaries AMPK and PGC 1 alpha support oxidative remodeling. - Hormone spikes are not the main driver of growth Acute testosterone and GH responses do not predict long term hypertrophy. - Adaptations are load and velocity specific Heavy loads maximize 1RM Ballistic intent improves power and early RFD High rep work improves local endurance Resistance training is not just muscle hypertrophy. It is coordinated plasticity from the cortex to the contractile protein. Train the signal, and the structure adapts. Learn more: https://lnkd.in/gCWKqGDs

Researchers are making major progress toward prosthetic arms that feel and move more like real limbs by decoding nerve commands that remain years after an amputation. After a limb is lost, the nerves that once controlled hand and finger movement don’t simply vanish. They continue to carry detailed motor signals from the spinal cord even though they no longer connect to a real hand. By surgically reconnecting these nerves to muscles in the remaining limb and implanting tiny electrode arrays, scientists can now capture the rich electrical language of individual motor neurons with unprecedented precision. In recent experiments, volunteers who had previously undergone targeted muscle reinnervation were asked to imagine moving their missing hand. The implanted microelectrodes recorded bursts of electrical activity deep within the reinnervated muscles linked to those imagined movements. Advanced algorithms then separated the mixed signals into patterns tied to specific intentions like bending a wrist or extending a finger. This level of neural detail has never before been achieved in people with long term amputations. The exciting finding is that complex movement plans survive long after limb loss and can be decoded into control signals for prosthetic devices. The ultimate goal is to create wireless implants that can send these signals in real time to next generation bionic limbs, allowing wearers to move artificial hands with the fluidity and natural control once thought impossible. Research Paper 📄 DOI: 10.1038/s41551-025-01537-y

Antibody guided RNA therapy provides a precision strike against myotonic dystrophy. An antibody oligonucleotide conjugate is a therapy that uses an antibody to deliver a genetic silencing molecule directly into muscle cells to shut down harmful RNA. Nicholas Johnson and colleagues describe in a new paper in the New England Journal of Medicine how an antibody oligonucleotide conjugate called del-desiran was tested in a phase 1–2 clinical trial for myotonic dystrophy type 1. The therapy targeted the toxic genetic message that was thought to be driving the disease. Key points: – Del-desiran successfully reduced levels of toxic DMPK messenger RNA in muscle tissue by up to 46 percent, showing the therapy reached its intended target and engaged the underlying disease mechanism. – The therapy improved abnormal RNA splicing patterns in muscle, especially at higher doses, which is important because missplicing is a key driver of muscle dysfunction in myotonic dystrophy. – Most adverse events were mild to moderate, however two serious adverse events occurred, including one stroke-like event that led to treatment discontinuation and this underscores the importance of ongoing safety monitoring. My take: This study represents a major milestone. For decades, delivering RNA therapies to muscle has been a barrier. This antibody guided delivery system appears to overcome that obstacle. The signals of molecular correction and early functional improvements suggest we may be entering an era where targeted RNA therapies could alter the course of inherited neuromuscular diseases. Larger and longer trials will be essential to determine the safety and the true clinical impact. Here are 5 points that resonated w/ me: 1- This therapy directly targets the root genetic cause of myotonic dystrophy rather than just treating symptoms. 2- The antibody acts like a delivery vehicle that guides the therapy precisely into muscle cells. 3- Improvements in muscle biology were measurable, even in this early stage trial. 4- Safety signals require careful monitoring and remind us early phase trials are designed to learn as much as possible. 5- This approach may open the door to treating many other genetic neurologic and muscle diseases using similar technology. https://lnkd.in/gmPPc-ek International Parkinson and Movement Disorder Society Society for Neuroscience

I'm thrilled to announce our latest research publication in Nature Communications unveiling the complexity of skeletal muscle fibers through advanced proteomics and transcriptomics. In this study, we analyzed over 1,000 individual muscle fibers, to explore the remarkable heterogeneity beyond traditional myosin heavy chain classifications. This work would have been impossible without the remarkable advances in proteomics over the last five years. Our findings reveal that metabolic, ribosomal, and cell junction proteins significantly contribute to the multidimensional variation among myofibers. Notably, while slow and fast fiber clusters are evident, our data suggest that type 2X fibers are not phenotypically distinct from other fast fibers. This achievement was made possible through a vast collaborative network, and we're grateful for the collective effort that brought this project to fruition. Novo Nordisk Foundation Center for Basic Metabolic Research Proteomics Research Infrastructure (PRI) link to article - https://lnkd.in/dhhdU73z

Brilliant work from Ewout Groen, Gijs van Haaften and the team at UMC Utrecht—advancing our understanding of spinal muscular atrophy (SMA). SMA has long challenged clinicians—not just in diagnosing and classifying the disease, but in predicting how patients will respond to therapy. Why? Because the SMN1/SMN2 region is so complex, so repetitive, that legacy technologies often fail to resolve it. This study used Oxford Nanopore’s ultra rich data and a new analysis pipeline, HapSMA, to phase and characterise individual gene copies across 31 SMA patients and 29 healthy controls. The result: • Widespread gene conversion from SMN1 to SMN2 in patients • Hybrid genes and structural variants previously undetectable • Copy-specific SNVs with diagnostic and therapeutic relevance • New prognostic insights—beyond simple copy number counts This matters for drug development: many SMA therapies target SMN2. If that gene is a hybrid or exists in a non-canonical regulatory context, therapeutic response may be far more variable than genotype alone suggests. From a translational perspective, this is a leap forward—not just for SMA, but for any disorder buried in the dark genome. The switch is ON. https://lnkd.in/emPab8zp

🧬📊 Sarepta Therapeutics #Reports #First Clinical #Data for #siRNA #Pipeline in FSHD1 & DM1 — Demonstrates Targeted Muscle Delivery with Favorable Safety A notable milestone in RNA therapeutics for neuromuscular diseases. Sarepta Therapeutics shared early Phase 1/2 data for SRP-1001 (FSHD1) and SRP-1003 (DM1), highlighting robust muscle delivery, early biomarker activity, and no dose-limiting toxicity using its αvβ6 integrin-targeted siRNA platform. 📊 Key highlights 1️⃣ 🧬 Targeted delivery breakthrough • αvβ6 integrin ligand enables high siRNA muscle concentration ➡️ Addresses long-standing delivery challenge 2️⃣ 📈 Early proof-of-concept • Single dose shows target protein/mRNA knockdown ➡️ Validates mechanism 3️⃣ 🛡️ Favorable safety profile • Mostly mild-to-moderate AEs • No dose-limiting toxicity observed 4️⃣ 🧪 Dose-dependent exposure • Increased plasma + muscle levels across doses ➡️ Supports scalability for efficacy 🗣️ Leadership perspective @Louise Rodino-Klapac, Ph.D, President, Research & Development and Technical Operations, Sarepta Therapeutics: “These results support the differentiated potential of this siRNA platform… and could meaningfully change the treatment landscape.” 🔍 Why this matters 1️⃣ 🚧 Solving the siRNA “delivery problem” ➡️ Muscle targeting has been a major bottleneck 2️⃣ 🧬 Expanding RNA therapeutics beyond liver ➡️ Moving into muscle + CNS diseases 3️⃣ 🧪 Broad pipeline potential • FSHD, DM1, IPF, Huntington’s, SCA ➡️ Platform play, not single asset 4️⃣ 🤝 Strategic foundation • Built on collaboration with @Arrowhead Pharmaceuticals 💡 My takeaway 1️⃣ Delivery is the real innovation in RNA ➡️ Targeting ligands > payload alone 2️⃣ Rare neuromuscular diseases are becoming tractable ➡️ First real disease-modifying potential emerging 3️⃣ Platform value > individual program value ➡️ Multi-indication scalability is key 4️⃣ Early-stage data, but high strategic signal ➡️ Investors will watch durability + efficacy closely 📌 Bottom line: 👉 Sarepta Therapeutics is positioning its αvβ6-targeted siRNA platform as a next-generation solution for muscle diseases, potentially unlocking a new wave of RNA therapies beyond traditional boundaries. #RNAtherapeutics #siRNA #RareDisease #Neuromuscular #Biotech #DrugDevelopment #PrecisionMedicine https://lnkd.in/gUwcw8Wh

[Editor’s Choice] Francesco Marzola, Nens van Alfen, Jonne Doorduin, Kristen M. Meiburger. Machine learning-driven Heckmatt grading in facioscapulohumeral muscular dystrophy: A novel pathway for musculoskeletal ultrasound analysis. Clinical Neurophysiology 2025;172:61-69. Open access: https://lnkd.in/gJXhW7GE Editor's commentary: Ultrasound is increasingly being used in the diagnosis and assessment of neuromuscular disorders. Applications of machine learning is a rapidly growing field in biomedical research and many studies have focused on medical imaging. In this volume of Clinical Neurophysiology, Marzola et al. analyzed over 25,000 ultrasound images from 290 facioscapulohumeral muscular dystrophy patients and normal subjects. An automated machine learning approach demonstrated high concordance with visual scoring by expert observers. The study demonstrated the potential for machine learning approach to improve the objectivity and efficiency of muscle ultrasound assessment. By Robert Chen Editor-in-Chief Clinical Neurophysiology

Our recent study, published in PNAS, introduces a wearable near-infrared patch that employs machine learning to enhance noninvasive muscle-tracking technology. By utilizing the strong light-muscle interaction and deep penetration of near-infrared light, the device addresses key limitations of existing state-of-the-art methods, such as indirect measurements and the need for specialized adhesives. This innovation opens new avenues for monitoring disease progression, assessing treatment effectiveness, and supporting rehabilitation efforts. We are excited to further explore its clinical applications through more clinical trials. Congratulations to Yihan Liu, Arjun Putcha, Gavin Lyda, Nanqi Peng, Salil Pai, Tien Nguyen, Sicheng Xing, Shang Peng, Yiyang Fan, Yizhang Wu, Wanrong Xie! We are grateful for support from National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Science Foundation (NSF), and North Carolina Biotechnology Center (NCBiotech). University of North Carolina at Chapel Hill UNC Research Department of Applied Physical Sciences at The University of North Carolina Link to the paper: https://lnkd.in/efdRB2ZY