Summermatter, S. | bioRxiv Science

bioRxiv2025

Exercise-Induced Myostimulin Enhances Muscle Function in Health and Disease

Musculoskeletal diseases are a leading contributor to years lived with disability worldwide1,2. While exercise offers significant benefits for people with these conditions, many individuals do not engage in adequate physical activity3. Consequently, there is growing interest in pharmacological interventions that can emulate essential health-promoting effects of exercise4,5. By integrating transcriptomics data of exercised skeletal muscle, we identified C1orf54/C1ORF54 as a novel exercise-responsive gene in mice and humans. We demonstrate that removal of the first sixteen N-terminal amino acids of C1ORF54 gives rise to a previously uncharacterized protein that stimulates the proliferation of muscle precursor cells and which we named myostimulin. Intriguingly, repeated intermittent treatment of mice with recombinant myostimulin boosts maximal isometric strength in mice within a week. Moreover, we have engineered a variant with improved biophysical properties, increased biological activity in vitro and enhanced efficacy in vivo. This variant even accelerates the recovery of muscle strength from axonotmesis, a condition associated with pronounced muscle weakness. Our data ascribe to myostimulin a role for enhancing the regenerative capacity of skeletal muscle and mediating functional adaptations characteristic of sustained resistance training. Therefore, myostimulin could be an innovative, fast acting therapeutic for certain human musculoskeletal diseases, injuries and other disorders that improve with exercise.

physiology↗

bioRxiv2025

Experimental Autoimmune Encephalomyelitis Causes Skeletal Muscle Dysfunction in Mice

Multiple sclerosis (MS) is a neuroinflammatory disease affecting the brain and spinal cord and characterized by demyelination, neurodegeneration and chronic inflammation. More than 90% of people with MS present with peripheral muscle dysfunction and a progressive decline in mobility. Current treatments attenuate the inflammatory processes but do not prevent disease progression. Therefore, there remains an unmet medical need for new and/or additional therapeutic approaches that specifically improve muscle function in this patient population. The development of novel treatments targeting skeletal muscle dysfunction in MS will depend on suitable preclinical models that can mimic the human musculoskeletal manifestations of MS. Using a non-invasive approach to assess muscle function, we demonstrate in vivo that Experimental Autoimmune Encephalomyelitis (EAE) impairs skeletal muscle strength. Our data reveal a 28.3% (p<0.0001) lower muscle force in animals with EAE compared to healthy control mice during electrically evoked tetanic muscle contractions that occur at intervals of 0.25 seconds and thus mimic fatiguing tasks. As we conduct force measurements by direct transcutaneous muscle stimulation in anesthetized animals, our setup allows for the repeated evaluation of muscle function, and in the absence of primary fatigue or reduced nerve input which constitute important confounding factors in MS. Taken together, our data highlight important similarities between MS in humans and EAE in mice with regards to skeletal muscle contractile impairments, and provide first evidence for a non-invasive in-vivo setup that will enable the preclinical profiling of novel drug candidates directed at specifically improving muscle function in MS.

physiology↗