Recipient organisationKing's College LondonSource-published name: King's College London
Funding£927K
PeriodAug 2025 — Aug 2028
In plain English
AI plain-English summary
A single muscle fibre can now be profiled for four different types of molecular data at once, revealing how specific subtypes of muscle cells go wrong in motor neuron disease. This matters because motor neuron disease (ALS) kills roughly 6 in every 100,000 people, and there is no cure. The field has long assumed the disease starts in the brain and spinal cord, then damages muscle secondarily. But growing evidence suggests muscle itself may be an active driver of the disease, not just a passive victim. Muscle tissue is complex, containing many cell types and fibre subtypes that behave differently in health and disease. Standard biopsy methods blend all these signals together, masking what individual fibres are doing. The new technique, called SMyoMFO, lets researchers measure a single fibre’s mechanical properties, its proteins, its gene activity, and its epigenetic regulation from the exact same cell. If this works, it could reveal early, fibre-type-specific molecular changes that precede nerve damage—potentially identifying new drug targets or biomarkers. The project also uses a pig model that mimics human ALS more closely than mice, making findings more translatable. This is fundamental science, but understanding how muscle itself contributes to ALS could open entirely new avenues for treatment.
View original technical description
Amyotrophic Laterals Sclerosis (ALS), characterised by destruction of upper/lower neurons and severe muscular wasting, is the most common motor neuron disease (prevalence ~ 6 cases/100,000 persons). Despite a surge in societal and Governmental interest, there remains no cure. ALS is thought to originate in upper centralised cells leading to skeletal muscle (SkM) denervation and muscle pathology. However, this belief has been questioned. Muscle of ALS animal models that preceded denervation and/or disease onset, show metabolic dysregulation, atypical muscle-specific transcriptional expression and reduced muscle volume, with further work showing denervation itself can be caused from intracellular defects within SkM. A growing body of evidence indicates SkM to be a key propagator in ALS aetiology. However, the tissue has received disproportionality low research attention, thus our understanding of SkM in ALS remains limited. This MRC NIRG project will tackle this shortfall. SkM is very complex, harbouring array of cell types including muscle specific cells (myofibers). Myofibers exist in a spectrum of sub-types, from type I (slow-type) to type IIB/X (fast-type), displaying divergent functional and molecular characteristics that further differ in disease states, with evidence suggesting that ALS myofibers are denervated in a subtype specific manner. The extent of myofiber subtype specific dysregulation across ALS disease-course remains unclear. Traditionally, SkM biopsies are examined in their entirety, capturing the molecular profiles of all the cell types and myofiber sub-types within the biopsy. This approach develops data that is non-specific to myofibers or sub-types and contains unnecessary noise when attempting to integrate multiple data types. While single cell approaches have been used in SkM, these methods are unable to capture full heterogeneity of myofiber populations and have been limited to a single data set per myofiber. New methodological approaches are required to provide deeper and more comprehensive understanding of ALS SkM. Building upon recent work, I developed a novel approach that enables the generation of four data sets from the exact same myofiber. Termed Single Myofiber Multi-Function Omics (SMyoMFO) analyses the biophysical properties of key sarcomeric protein, coupled with cell-wide proteomic and transcriptomic expression and epigenomic regulation of DNA. Crucially, all data originate from the exact same myofiber. We will use SMyoMFO to answer the hypothesis that a coordinated metabolic and molecular dysregulation occurs in a myofiber sub-type specific manner with these defects occurring early in disease-course. Aim 1. To examine the integrated dysregulation of specific myofiber subtypes in human ALS SkM. Aim 2. Analyse the myofiber subtype specific dysregulation in an animal model of ALS disease course. We will generate SMyoMFO data from control and symptomatic ALS human SkM samples (WP 1.1) ascertaining the heterogeneity in dysregulation across the myofiber subtype spectrum (WP 1.2). Due to ALS rarity, studying disease-course in human muscle is near impossible. We will therefore develop SMyoMFO data (WP 2.1) from a recently developed swine-model of ALS that best represents human pathology, analysing myofiber subtypes in pre-symptomatic and symptomatic muscle to understand disease course dynamics (WP 2.2). Combining human and swine-model data, we will determine the conserved dysregulation across species identifying translatable myofiber subtype markers in ALS (WP 2.3). This project will use bespoke methodology to provide unprecedented analyses of the extent of dysregulation in ALS SkM, promising to open up a vista of research and therapeutic opportunity in the disease field.
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