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Nourishing Muscles: The Quest for Novel Bioactives to Improve Muscle Health

Muscle is an indispensable organ for glucose uptake and storage, and it is also a reservoir of amino acids stored as protein. Maintenance of muscle health is crucial for overall physical function, metabolism, bone and joint health, blood sugar regulation, cardiovascular health, mental well-being, and longevity. Traditionally, dietary protein has been a major source for muscle maintenance, but increasingly bioactives from natural sources are being investigated to cater to diverse muscle health conditions. Identification of these novel solutions also requires development of new technologies, validation methods and business models targeting specific consumer categories.

The challenge with discovering nutritional bioactives for muscle health


Products aimed at improving muscle performance and health cater to a diverse range of consumer categories, reflecting the wide variety of needs and goals across different segments of the population. Some of the primary consumer categories relevant for these products include:

Athletes and Fitness Enthusiasts: This category includes individuals engaged in various sports and fitness activities, such as weightlifting, bodybuilding, running, cycling, and team sports. Products targeting athletes and fitness enthusiasts aim to enhance muscle strength, endurance, recovery, and overall performance.

Aging Population: As people age, maintaining muscle mass, strength, and functionality becomes increasingly important for preserving independence and quality of life. Products targeting the aging population aim to support muscle health, mobility, and functional capacity.


Weight Management: Products targeting weight management often include components aimed at preserving lean muscle mass while promoting fat loss. A recent case in point is the growing evidence that the weight loss drug Ozempic causes significant loss of muscle mass. Products in this category need to support metabolism and energy expenditure while preserving muscle tissue. [1]


Special Populations: Certain populations, such as individuals with chronic diseases, mobility impairments, or specific dietary needs, may require tailored products to support muscle health and performance. Examples include nutritional supplements formulated for individuals with sarcopenia (age-related muscle loss), and cachexia (cancer-induced frailty). [2]


Health and Wellness Seekers: Individuals focused on overall health and wellness may seek products that support muscle health as part of a holistic approach to well-being. These products often emphasize natural ingredients, sustainability, and transparency in sourcing and manufacturing.


Given the diverse consumer categories, customized muscle health solutions are needed that address the specific physiological differences between population segments. Complicating this task is also the potential diversity of natural ingredients available for improving muscle health. Thus, new technologies that are fast, efficient and cost-effective are needed in the search for bioactives that dramatically enhance muscle health. 


C. elegans – a preclinical model with human-relevant muscle physiology


In the vast and intricate tapestry of biological research, the humble nematode Caenorhabditis elegans (C. elegans) occupies a place of distinction, especially when it comes to unraveling the complexities of muscle biology. This tiny, transparent roundworm, no longer than a millimeter, has become one of the most valuable tools in biological research, offering profound insights into the fundamental mechanisms of muscle function, disease, and aging. 


Living muscle fibers in transgenic C. elegans visualized using fluorescent reporters (Credit: Ryan Littlefield, Biophysical Society Blog, 2017.) 

At first glance, the musculature of C. elegans might seem worlds apart from that of humans. Yet, beneath this superficial dissimilarity lies a surprising degree of conservation in the fundamental aspects of muscle biology. The basic unit of muscle fiber, the sarcomere, shows remarkable similarity in structure and function between C. elegans and humans, including the arrangement of actin and myosin filaments. Similar to humans, muscle forces in C. elegans rely on the acto-myosin contractility. [3]


Muscle cell aging visualized using a MYO-3::GFP translational fusion highlighting the myosin heavy chain A in body wall sarcomeres from a young day 1 adult (A) and an aged day 15 adult, with evidence of sarcomere disorganization (B). (Image source: Herndon et al., 2002.) 

Similar to mammals, the muscle function in C. elegans declines with age. The nematodes locomotory velocity is slowed down as well as their swimming prowess. Fluorescent visualization of the muscle fiber shows organized striations, however, with age, breaks appear in the sarcomeres. Thus, the essential features of an aging muscle can be replicated in C. elegans.


Why has C. elegans emerged as a model organism for studying muscle biology? The answer lies in its simplicity and the genetic tractability it offers. With just 959 somatic cells [4], of which a significant portion are muscle cells, Studies in C. elegans have shed light on critical aspects of muscle biology that are relevant to human health. For example, the role of calcium signaling in muscle contraction, the insulin/IGF-1 signaling pathway's impact on muscle growth and metabolism, mitochondrial dysfunction and the genetic underpinnings of muscle development and repair are all areas where C. elegans research has provided crucial insights. [5] 


The muscle physiology in C. elegans  is conserved including the muscle contraction mechanism, excitation-contraction coupling and neuromuscular junctions. Molecular processes involving calcium signaling, neurotransmitter release, and neural signal transmission are conserved. [6]


With NemaLife platform, discovering nutritional bioactives for muscle health takes few weeks and not years


Traditional animal testing with rodents is slow, inefficient and is not suited for high throughput screening. However, C. elegans a short-lived microorganism with conserved muscle biology can enable rapid in vivo evaluation of efficacy of bioactives. At NemaLife, we use a C. elegans based platform that integrates microfluidics for nematode culture, and a visual AI to autoprocess millions of video images to generate phenotypic data at scale. Our organism-on-chip platform is a revolutionary advance to prioritize qualified nutritional bioactives for human studies in few weeks.

 

NemaLife’s organism-on-chip platform is validated to quantify several endpoints related to muscle health. In humans, muscle health is maintained using different forms of locomotion (running, swimming, resistance training etc..). Likewise, C. elegans can be exposed to different mechanical environments to phenotype muscle performance, providing a robust means to evaluate efficacy of bioactive candidates.



Our microfluidic chip allows culture of adult nematodes across life, allowing us to phenotype young as well as aged organisms. Our visual AI engine NemaStudio.ai detects and tracks these crawling organisms providing locomotory measures. Bioactives that improve muscle performance cause organisms to move with enhanced crawling velocity. Since the locomotory prowess can be tracked as the population ages, we can quantify age-induced decline in muscle function, providing an elegant means to identify nutritional solutions for sarcopenia.



AMusVID 1. C. elegans movement declines during aging. Videos of swimming wildtype C. elegans (Top) young adults (day 4) and (Bottom) old adults (day 15). The swimming movement is termed “thrashing” and can be manually counted or computationally analyzed in detail. Thrashing rates decline as the animals age. (Video Source: C.I. Ventoso and M. Driscoll, Rutgers University; Restif et al., 2014; Ibáñez-Ventoso et al., 2016)



In liquid, C. elegans thrashes performing movement similar to swimming. Here, the propulsive thrust generated by the nematode body needs to be counter-balanced by the hydrodynamic forces in the liquid to swim elegantly. Additionally, thrashing rates decline in older organisms due to weakened muscles. Thus, swimming measures complement the crawling data, providing a different dimension into muscle physiology and how bioactives can improve their physiology.


Future of sustainable bioactive discovery


With the rise in conscious consumer health, and a growing aging population across the globe, maintenance of muscle health is of paramount importance. Identification of efficacious health solutions is critical to improve muscle integrity and performance. Diverse range of bioactives including biotics, phytochemical compounds and botanicals can be screened along with their combinations to target specific consumer segments. NemaLife’s organism-on-chip platform is compound agnostic, has high throughput, and a perfect match to sustainably discover novel bioactives that can be commercialized into functional ingredients.


Citations


1. Ida S, Kaneko R, Imataka K, Okubo K, Shirakura Y, Azuma K, Fujiwara R, Murata K. Effects of Antidiabetic Drugs on Muscle Mass in Type 2 Diabetes Mellitus. Curr Diabetes Rev. 2021;17(3):293-303. doi: 10.2174/1573399816666200705210006. PMID: 32628589.


2. Jang YJ. The Effects of Protein and Supplements on Sarcopenia in Human Clinical Studies: How Older Adults Should Consume Protein and Supplements. J Microbiol Biotechnol. 2023 Feb 28;33(2):143-150. doi: 10.4014/jmb.2210.10014. Epub 2022 Oct 31. PMID: 36474318; PMCID: PMC9998208.


3. Herndon, L.A., Wolkow, C.A. and Hall, D.H. 2023. The aging muscle. In WormAtlas. doi:10.3908/wormatlas.


4. Gilbert SF. Developmental Biology. 6th edition. Sunderland (MA): Sinauer Associates; 2000. Early Development of the Nematode Caenorhabditis elegans.

5. Murphy CT, Hu PJ. Insulin/insulin-like growth factor signaling in C. elegans. In: WormBook: The Online Review of C. elegans Biology [Internet]. Pasadena (CA): WormBook; 2005-2018.


6. Gieseler K., Qadota H., and Benian G. M. Development, structure, and maintenance of C. elegans body wall muscle. (April 13, 2017), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.81.2.


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