​​Even as the prevalence of sarcopenia rises with Singapore's ageing population, current therapeutics options are suboptimal in effectively treating the condition. At the SingHealth Duke-NUS Regenerative Medicine Institute of Singapore, a different approach based on regenerative medicine is underway with the aim that an individual's unique clinical, molecular and lifestyle data will be key to combating the condition.

INTRODUCTION

Sarcopenia is one of the most prevalent health problems among the elderly in the ageing population of Singapore, which will put unprecedented pressure on our healthcare system.

First introduced by Irwin Rosenberg in 1989 as the age-related loss of muscle mass, it has recently been recognised as a disease state that has its own ICD-10 (International Classification of Diseases, Tenth Revision) code in 2016. This age-related process of quantitative and qualitative muscle loss is now considered the precursory process of clinical frailty.

Clinical frailty is not only associated with a poorer quality of life (QOL), but also increased hospitalisation and increased risk of surgical morbidity and mortality.

Prevalence in Singapore

Two recent epidemiological studies in Singapore, the Yishun Study and GERI-LABS 2 study, found that the prevalence of sarcopenia in the local community is between 27.0-32.2%.

In addition, those with sarcopenia were unsurprisingly associated with increased age, frailty and type 2 diabetes mellitus.

Diagnostic assessment

The Asian Working Group for Sarcopenia (AWGS) and European Working Group on Sarcopenia in Older People (EWGSOP) have both acknowledged the clinical significance and impact of sarcopenia in age-related and disease-related degeneration leading to frailty.

In 2019, both societies refined their research-oriented assessment and termed it as the Clinical Research Diagnostic Algorithm for Sarcopenia. It utilises a combination of objective measurements of appendicular skeletal muscle mass, muscle strength and physical performance.

For screening in the community, AWGS has recommended the inclusion of a simple measurement of calve circumference (for ambulant individuals) into their algorithm, improving the ease of sarcopenia screening.

Skeletal muscle has one of the most complex structures and intricate organisations, constituting pproximately 40% of body mass. Not only does the muscle contract to enable locomotion, but it also modulates a plethora of biological networks that are essential to maintain human health.

Hence, any form of muscular disorder severely affects the QOL of patients as it compromises muscle architecture and contractile performance.

CURRENT TREATMENTS AVAILABLE

Unfortunately, there is a dearth of effective therapeutics available for muscle diseases, with exercise and nutritional interventions remaining the cornerstone of treatment.

This can be largely attributed to the frustrating series of failed clinical trials that pharmacologically target specific pathways to eradicate muscle diseases. Most of these drugs could neither translate into a significant increase in muscle size nor elicit any functional improvement.

1. Pharmacological treatments

To date, commonly prescribed drugs to treat certain muscle diseases include a combination of growth hormone and testosterone.

Limitations

However, there is mounting evidence that these therapies elicit marginal beneficial outcomes with minimal changes in body composition and strength. In addition, these treatments have considerable side effects, limiting application in clinical practice.

Despite the setbacks, there are still massive efforts to develop pharmacological drugs to treat skeletal muscle atrophy due to the vested interest from pharmaceutical companies, as muscle remains an undermedicated organ.

The drug development pipeline for muscle diseases includes myostatin/activin receptor type IIB signalling inhibitors, muscle troponin complex activators, exercise mimetics and anabolic stimulants.

2. Nutritional interventions

One underlying cause of muscle wasting can be attributed to malnutrition or nutrient deficiencies such as in vitamin D or B12. Malnutrition is a key pathophysiological driver of sarcopenia, exacerbating muscle wasting in elderly patients.

Recommendation

The International Conference of Frailty and Sarcopenia Research (ICFSR) International Clinical Practice Guidelines for Sarcopenia recommend that clinicians consider protein supplementation or a protein-rich diet for treatment of sarcopenia in older adults.

Several studies have demonstrated that branched-chain amino acids, whey protein, leucine and its metabolite ß-hydroxy ß-methylbutyrate (HMB) can improve muscle mass and strength in specific clinical populations and in sarcopenic patients. Even though the principal findings of these studies have garnered traction among clinicians, the quality of evidence is still subpar, warranting further investigation with higher quality study design.

Other promising nutritional interventions that can potentially attenuate muscle loss in clinical populations include fish oil-derived, long-chain omega-3 polyunsaturated fatty acids and multivitamin/multimineral supplements.

3. Exercise prescription

Different modalities of exercise remain the foundation for improving cardiovascular fitness, inducing muscle hypertrophy and increasing strength in patients with sarcopenia. Mechanistically, both aerobic and resistance exercises have been shown to induce mitochondria biogenesis, ATP production and protein synthesis, and to supress catabolic networks.

The COVID-19 pandemic, in which physical activity is restricted thus promoting sedentary behaviour, can further result in the loss of muscle mass and function in geriatric patients.

Recommendation

ICFSR recommends that seniors participate in a progressive physical activity programme which encompasses a resistance training element.

Limitations

Clinically, there is no consensus on an effective exercise prescription, and it is incumbent on healthcare professionals to formulate individualised intervention to optimise treatment outcomes.

In addition, patients with underlying health conditions may lack intrinsic motivation to adhere to the strict physical programme, rendering the need to pivot towards an alternate therapy that is suboptimal.

​Finding a Cure Beyond the Current Therapeutics

Overall, pharmacological options have shown minimal benefits and considerable side effects, with many clinical trials yielding poor outcomes.

Thus, the SingHealth Duke-NUS Regenerative Medicine Institute of Singapore (REMEDIS) aims to rejuvenate the field through a comprehensive approach to muscle research and stem cell therapy development. By building an increased knowledge of sarcopenia, REMEDIS aims to drive the discovery of more effective biomarkers and better interventions.

MULTI-OMIC APPROACH TO FURTHER UNDERSTAND SARCOPENIA

Due to the limitations of current treatments, it may be critical to rethink our strategy in developing innovative therapeutics strategies by first galvanising the field of muscle research.

A radical shift in research direction is warranted, and our laboratory has taken a comprehensive, multipronged approach to study muscle diseases, which is often systemic and multifarious in nature.

To date, we have established a muscle-specific repository to address the need for sarcopenia research, which we believe is the first of its kind in Singapore.

The strategy will be to perform multi-omic profiling of these muscle materials in an effort to unravel the regulatory and signalling networks involved in the pathogenesis of sarcopenia.

Interrogating epigenetic factors, for example, can potentially open a new avenue for drug discovery and therapeutics, as several bodies of evidence suggest that epigenetic changes are a major contributor to the development of sarcopenia.

We aim to discover novel biomarkers for relevant cohorts by further leveraging on this biorepository of sarcopenia-specific biomaterials including serum.

A combination of tissular and serum biomarkers in tandem with anthropomorphic and imaging measurements will address an unmet clinical need that will greatly improve the prediction, diagnosis, prevention and management of sarcopenia.

DEVELOPING STEM-CELL-BASED THERAPIES

Another research goal of ours is to develop stem-cell-based therapies that have long been heralded as a promising means to treat incurable diseases since the discovery of induced pluripotent stem cells (iPSCs), which led to a paradigm shift in the field of regenerative medicine.

However, optimism has since dwindled as the effectiveness and success of iPSCs are still under intense scrutiny. This is especially apparent when attempting to generate myogenic cells from stem cells, whereby a multitude of limitations impede the progress towards utilisation in clinical trials for muscle repair.

To date, our team has established a scalable serum-free platform for the directed differentiation of human PSCs into a homogenous population of myotubes, eliminating the need for transgene overexpression.

BIOENGINEERING 3D MYOFIBER ORGANOIDS

To further recapitulate key phenotypic and functional aspects of human skeletal muscle, our team has demonstrated the ability to bioengineer 3D myofiber organoids that manifest mature contractile apparatus.

Using this platform, we are able to model the human features of a chronic metabolic disease, and identify both its pathogenic mechanism and therapeutic targets. To highlight the potential to translate these findings into clinical settings, these muscle organoids have been successfully engrafted in preclinical models.

 

CONCLUSION

The translation of findings from laboratory benches to the patients' bedside is often challenging. However, elucidating the mechanistic underpinnings of sarcopenia will improve clinicians' understanding of the multiorgan, multifactorial process of age-related muscle loss. In doing so, synergistic collaboration between clinicians and basic scientists can lead to the discovery of more effective diagnostic and prognostic biomarkers.

Increased knowledge of sarcopenia and its management will improve interventions that can be tailor-made to different stages of sarcopenia – a step towards precision medicine. It is conceivable that a multimodal, multidisciplinary approach based on an individual's unique clinical, molecular and lifestyle data will be key to combating this increasing health problem in our ageing population.

 

Professor Teh Bin Tean is the Co-Director of the SingHealth Duke-NUS Regenerative Medicine Institute of Singapore, Deputy Medical Director (Research) at the National Cancer Centre Singapore and Principal Investigator of the Laboratory of Skeletal Muscle Regeneration.

 

Assistant Professor Frederick Koh is an Associate Consultant in the Colorectal Service, Department of General Surgery, Sengkang General Hospital. His clinical interests include the various aspects of colorectal surgical oncology, proctology as well as acute care surgery. Apart from clinical contributions, Prof Koh places emphasis on the importance of academic surgery. He is published in numerous peer-reviewed journals, and enjoys both clinical and basic science research pertaining to the fields of General and Colorectal Surgery. He has held grants and has experience in conducting both population-based and trial-based research, and intends to continue his pursuit of academia in order to continue participating in the continuous improvement of clinical practice to serve his patients best. He is currently pursuing a PhD with Duke-NUS around the theme of sarcopenia in surgical patients.

 

Dr Chua Min Wen Jason is a Research Fellow at the Division of Medical Sciences at the National Cancer Centre Singapore. His research interests focus on modulating stem cells into muscle organoid to model muscle disease and to unravel novel signalling networks driving the progression of sarcopenia. In addition, Jason is passionate about sustainable food-tech innovation, with a special interest in cultured meat research to address the issue of food security in land-scarce Singapore.

 

GPs can contact the SingHealth Duke-NUS Cell Therapy Centre at sd.cell.therapy@singhealth.com.sg to know more about the available cell therapies and clinical trials on the SingHealth campus.