Muscle fibres are the motors that power our movements, allowing us to walk, run, eat or hug a loved one. But the extracellular matrix (ECM), a dynamic and complex network of proteins and molecules within which our fibres are housed, is now known to play an essential role in muscle function, growth, injury recovery and ageing.
Measuring cellular activities within the ECM may potentially inform targeted physical activity treatments aiming to improve ECM status and enhance disease treatment. Yet these potentially important biomarkers are still underused in both research and clinical environments.
The ECM may be the next place to search for clues on how to improve muscle function and delay or overcome the effects of ageing and disease.
Muscle disuse in response to inactivity, injury or ageing can trigger non-optimal changes in the ECM including muscle connective tissue proliferation leading to stiffness and immobility. However, maintaining the muscle at a longer length during immobilisation can attenuate negative outcomes, and these are clearly visible through ECM biomarker assessments.
Even a single exercise session can evoke powerful changes resulting in improvements in muscle ECM biomechanical and physiological properties These benefits are amplified when exercise is repeated over time.
Due to a lack of research, many questions remain regarding muscle ECM biology and its implications for human health and physical function. It remains unclear which exercises are best for stimulating ECM remodelling or collagen synthesis, which biomarkers can accurately assess ECM status or how alterations in the ECM affect responses to acute or long-term exercise regimes, disuse, or ageing.
We also lack an understanding as to how these adaptations affect muscle function in terms of injury recovery, health maintenance, and physical performance enhancement.
With numerous biomarkers readily available, practitioners should be well informed about interpreting the data correctly. For example, a change in the abundance of a biomarker examined in blood may provide different information to that same biomarker being examined in muscle tissue, e.g. an increase in blood hydroxyproline concentration (a molecule present in all types of collagen) may indicate increased collagen breakdown, while increased muscle hydroxyproline indicates increased muscle collagen content. Awareness of these intricacies is critical before interpreting changes in biomarker levels.
What are the best biomarkers
Promising blood, urine and even sweat biomarkers for ECM remodelling, ECM status, and exercise, disuse and ageing effects are shown in figure 1. In humans, collagen fractional synthesis rate appears to be the most consistent biomarker for assessing acute collagen synthesis, whereas collagen IV and hydroxyproline appear to be reliable for assessing acute collagen breakdown.
This may be relevant in diseases where collagen turnover assessment is important, such as muscular dystrophy, rheumatoid arthritis, or Ehlers–Danlos syndromes.
Additionally, integrin-α7, tenascin-C, and collagen IV in tissue samples can be used to reliably assess acute changes in the basal membrane, ECM-to-cell adhesion, and the collagen scaffold itself, respectively. Hydroxyproline and prolyl 4-hydroxylase also appear reliable for assessing long-term collagen synthesis, whereas integrin-β1 increases consistently with long-term exercise and indicates changes in cell-to-ECM anchorage.
Such changes can translate to novel treatments for diseases; (e.g. increased integrin content in mice with muscular dystrophy can dramatically reduce the severity of dystrophy symptoms).
Currently, no reliable human biofluid markers exist for the assessment of long-term ECM adaptations, so more research is needed. Promising candidate biofluid markers include P3NP and TGF-β for assessing collagen synthesis and hydroxylysylpyridinoline for assessing changes in collagen’s structural profile (i.e. optimally linked collagen vs collagen that linked via glycation, which is stiffer and prone to injury and disease).
ECM markers for disuse and ageing are also yet to be established, but data from animal studies suggest that prolyl 4-hydroxylase and galactosylhydroxylysyl glucosyltransferase might be promising indicators of collagen synthesis changes. Nevertheless, muscle ICTP, PINP, and MMP2 for disuse and galactosylhydroxylysyl glucosyltransferase for ageing are promising human biomarkers of collagen synthesis that remain to be explored.
Future perspectives
Hopefully, in the next few decades, researchers and practitioners will better understand the immense potential of muscle ECM on responses and adaptations to disease, exercise, injury, and ageing. So far, we have largely ignored much of what happens inside the muscle fibre within the ECM. Further research may inform us how to better target and stimulate this muscle domain, leading to new ways to train rehabilitate muscles, and even treat diseases.
This new era of understanding could potentially revolutionise how we approach health care by providing personalised strategies based on each individual’s unique biochemical fingerprint from their ECM response profile.
Key messages
- Muscle extracellular matrix (ECM) may be key for physical activity treatments and enhancing disease treatment
- Even a single exercise session can evoke powerful changes resulting in improvements in muscle ECM biomechanical and physiological properties
- Several ECM biomarkers can assess different aspects of ECM status and changes in response to exercise, disuse, and disease. Beware intricacies of interpretation before using them.
ED: Dr Mavropalias is a researcher at ECU and Murdoch University and Prof Blazevich is from ECU.
Author competing interests – nil