Most of us think about muscles in terms of movement.
They allow us to walk, run, lift objects or simply stand upright. But beneath every movement lies another function that often goes unnoticed: muscles are constantly sensing the physical world around them.
Every contraction, every step and every change in posture generates mechanical signals. Muscle cells detect these forces and convert them into biological responses that help maintain tissue structure, regulate metabolism and adapt to changing demands.
This remarkable ability is known as mechanotransduction, and understanding how it works has become one of the most active areas of muscle biology research.
A recent review published in EMBO Reports, supported by the Horizon Europe project DREAMS, explores this process in depth. Rather than reporting new experimental findings, the review brings together current evidence to explain how skeletal muscle responds when mechanical loading is reduced and highlights the biological questions that researchers are still working to answer.
Although the review focuses on conditions such as microgravity and prolonged muscle unloading, its conclusions extend well beyond space research. They provide valuable insight into biological processes that are also relevant to muscle degeneration, ageing and neuromuscular disorders.
Muscles are constantly interpreting mechanical information
For many years, muscle loss was largely viewed as a simple consequence of reduced activity.
If muscles were not being used, they gradually became smaller and weaker.
Research over the last two decades has revealed a much more sophisticated picture.
Muscle cells do not merely react to inactivity. They continuously monitor their mechanical environment through an interconnected network of biological structures that includes the cell membrane, the cytoskeleton, the extracellular matrix and specialised mechanosensitive proteins.
These structures allow muscles to detect changes in physical forces and rapidly adjust cellular behaviour in response. When normal mechanical stimulation is maintained, anabolic pathways help preserve muscle mass and function. When those signals decrease, a coordinated biological programme begins to favour protein degradation, structural remodelling and metabolic adaptation.
One of the most interesting messages emerging from the review is that there is unlikely to be a single “mechanical sensor” responsible for this process.
Instead, multiple systems appear to work together, integrating mechanical information before triggering broader cellular responses.
This systems-level perspective is becoming increasingly important because it helps explain why muscle degeneration involves many interconnected pathways rather than one isolated molecular event.
Why study muscle in microgravity?
At first glance, studying muscles in space may seem disconnected from everyday medicine.
In reality, it offers researchers something extremely valuable.
Microgravity dramatically reduces the mechanical forces that normally act on skeletal muscle. As a result, muscle tissue undergoes rapid structural and molecular changes over a relatively short period of time.
This makes spaceflight a powerful biological model for understanding how muscles respond when mechanical stimulation is removed.
Importantly, many of the same mechanisms are also observed in situations much closer to everyday clinical practice.
Patients confined to prolonged bed rest, individuals recovering from severe injuries requiring immobilisation and older adults experiencing age-related muscle loss all undergo substantial reductions in mechanical loading.
While these conditions differ considerably in their clinical presentation, they share biological processes that influence how muscle tissue adapts, remodels itself and, in some cases, progressively degenerates.
Understanding these shared mechanisms is therefore relevant across multiple areas of biomedical research.
Looking beyond individual signalling pathways
One of the strengths of this review is that it moves away from searching for a single explanation.
Instead, it proposes an integrated framework in which mechanical signals influence multiple biological systems simultaneously.
Changes in membrane tension affect signalling complexes located at the cell surface. Alterations in cytoskeletal organisation modify how forces are transmitted throughout the cell. The extracellular matrix remodels in response to changing mechanical conditions, while mechanosensitive ion channels contribute to regulating intracellular signalling.
Together, these processes shape gene expression, protein turnover and cellular metabolism, ultimately determining how skeletal muscle adapts to reduced mechanical loading.
This broader perspective also helps explain why targeting only one signalling pathway has often produced limited success in experimental models of muscle atrophy. The biology appears to be considerably more interconnected than previously thought.
Why this matters for neuromuscular disease research
Understanding how muscles interpret mechanical signals is not only relevant for studying the effects of spaceflight or prolonged inactivity.
It also helps researchers better understand the biological environment in which many neuromuscular disorders develop.
Muscle degeneration is rarely driven by a single molecular event. Instead, it results from multiple interconnected processes involving protein homeostasis, cellular organisation, metabolism and tissue remodelling.
The review highlights how mechanical signals interact with several of these biological processes, including cytoskeletal organisation, extracellular matrix remodelling and autophagy, all of which play important roles in maintaining healthy muscle tissue.
Although many questions remain unanswered, this growing body of knowledge provides researchers with a broader framework for investigating why muscle tissue progressively loses its structure and function under different conditions.
Where does DREAMS fit into this picture?
The DREAMS project investigates rare neuromuscular disorders through a combination of induced pluripotent stem cell (iPSC) models, artificial intelligence and molecular biology.
Rather than studying each disease in isolation, the project seeks to identify biological mechanisms shared across multiple rare neuromuscular disorders, with the long-term objective of supporting the identification of new therapeutic opportunities through drug repurposing and AI-based target discovery. Within this context, publications such as this review play an important role. They help consolidate current scientific knowledge, identify gaps in our understanding and provide a clearer conceptual framework for interpreting future experimental findings.
Importantly, the review does not present new experimental results generated by DREAMS itself. Instead, it brings together evidence from spaceflight studies, immobilisation models and basic muscle biology to explain how reduced mechanical loading influences muscle function across multiple biological levels.
For a research project like DREAMS, which aims to better understand the mechanisms underlying rare neuromuscular diseases, this broader scientific perspective is highly valuable.
Scientific progress often begins with better questions
One of the most interesting aspects of the review is not the number of mechanisms it describes.
It is the number of questions it leaves open.
How do muscle cells distinguish between temporary changes in mechanical loading and long-term degeneration?
Which mechanosensitive pathways are activated first?
Can these signalling networks be modulated before irreversible muscle damage occurs?
Answering these questions will require collaboration across multiple scientific disciplines, including cell biology, biomechanics, molecular medicine, artificial intelligence and computational biology.
This multidisciplinary approach reflects the direction in which muscle research is moving today.
Rather than focusing on isolated pathways, researchers increasingly seek to understand how complex biological systems interact to determine muscle health and disease.
Looking ahead
Progress in biomedical research rarely comes from a single discovery.
More often, it comes from gradually connecting knowledge across different fields.
By integrating evidence from cellular biology, mechanobiology and muscle physiology, this review offers a valuable synthesis of how skeletal muscle responds to changes in its mechanical environment.
For the DREAMS consortium, it also illustrates the importance of studying muscle biology from multiple complementary perspectives.
As researchers continue exploring the mechanisms that underlie rare neuromuscular disorders, building this integrated understanding will remain essential for guiding future research and, ultimately, for identifying new therapeutic strategies.
