Expanding diverse horizons in smooth muscle research: a symposium review of “Muscle and Pathology/Health: Frontiers of Translational Research” at the 66th Annual Meeting of Japan Society of Smooth Muscle Research

Abstract

Smooth muscle research is at the forefront of translational science, bridging the gap between basic molecular discoveries and clinical applications. The symposium “Muscle and Pathology/Health: Frontiers of Translational Research” at the 66th Annual Meeting of Japan Society of Smooth Muscle Research showcased recent advances in this field. The presentations highlighted diverse topics, including molecular targeting in malignant hyperthermia, the therapeutic potential of probiotics in inflammatory bowel disease, sex differences in pulmonary hypertension and the impact of dietary components on vascular health. These studies underscore the importance of precision therapies, personalized medicine and functional foods in understanding and managing diseases. As technological innovations continue to drive research, the symposium provided insight into future directions, such as developing targeted molecular therapies, leveraging probiotics for systemic effects, expanding sex-based studies, and industrializing outcomes of basic science. The findings presented offer promising avenues for new treatment strategies that could revolutionize smooth muscle-related healthcare, emphasizing the potential for improved patient outcomes through translational research.

Concept of the Symposium

Translational research plays a critical role in advancing the understanding of smooth muscle function and its implications for health and disease. Smooth muscle tissue, present in the walls of blood vessels, the gastrointestinal tract, and other organ systems, is essential for regulating vital physiological processes such as blood flow, digestion, and respiration. Dysregulation of smooth muscle function can result in a variety of pathologies, including pulmonary hypertension, gastrointestinal disorders and life-threatening vascular diseases.

The symposium “Muscle and Pathology/Health: Frontiers of Translational Research” at the 66th Annual Meeting of Japan Society of Smooth Muscle Research, showcased leading experts in smooth muscle-related biology, exploring cutting-edge research that bridges basic science and clinical application. While much of the focus was on smooth muscle dysfunctions, such as those seen in pulmonary hypertension and gastrointestinal disorders, the inclusion of Dr. Toshiko Yamazawa’s work on skeletal muscle and malignant hyperthermia added valuable insights into broader muscle pathologies and reminded us that at some extent regulatory components are indistinguishable between two systems (1). By incorporating these diverse perspectives, the symposium provided a comprehensive view of how muscle dysfunctions can be addressed through translational research, ultimately improving patient outcomes. This review summarizes the key findings presented at the symposium, explores the broader themes that emerged, and considers the future directions for smooth muscle research.

What Have We Learned from the Symposium? —Highlights of the Symposium Talks

Molecular Mechanisms of Malignant Hyperthermia: Dr. Toshiko Yamazawa presented her research on malignant hyperthermia (MH), a condition linked to dysregulation in the Ca²⁺-induced Ca²⁺ release (CICR) (2) due to mutations in the ryanodine receptor (RyR1) (3). Using a mouse model with a RyR1 mutation (4), her research team demonstrated that inhibiting this receptor could prevent MH symptoms. Based on the outcomes of the work, she proposed a new pathologic model of MH, a heat-induced Ca²⁺ release, which has been interrogated by a fluorescence temperature maker (5). This study highlights the importance of targeting molecular pathways in the treatment of smooth muscle-related diseases. Her research demonstrated how targeting specific molecular pathways, such as the ryanodine receptor, can offer new therapeutic avenues for treating life-threatening muscle disorders. This approach holds promise not only for MH but also for other diseases where smooth muscle dysfunction plays a central role.

Probiotics and Gut Health in Inflammatory Bowel Disease: Dr. Lin-Hai Kurahara’s research investigated the role of breast milk-derived probiotics in managing inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). The international collaboration focused on the probiotic Lactobacillus rhamnosus Probio-M9, which was shown to reduce intestinal inflammation and CAC in mouse models (6, 7). This research highlights the therapeutic potential of probiotics in modulating gut smooth muscle function and reducing inflammation. The key findings involve 1) that Probio-M9 suppresses the decreased expression of tight junction proteins and mitochondrial dysfunction caused by lipopolysaccharide (LPS) in colon cancer cell line Caco-2, and 2) that the Probio-M9 strain contains a useful enzyme, L-rhamnose isomerase, which can be used for rare sugar production. Using the recombinant L-rhamnose isomerase in Probio M9, this enzyme was shown to exhibit enzyme activity even under acidic conditions, and the X-ray crystal structure of the complex with rare sugar was also successfully analyzed (8). In addition, the data presented suggest prebiotic functions of lactulose, a derivative of lactose (9) on IBD and CAC. Her enthusiastic presentation reinforced the emerging understanding that the gut microbiome plays a critical role in health and disease. The potential for probiotics to modulate smooth muscle function and reduce inflammation in the gut suggests that microbiome-based therapies could become a mainstay of treatment for gastrointestinal disorders like IBD.

Sex Differences in Pulmonary Hypertension: Dr. Aya Yamamura’s presentation focused on pulmonary arterial hypertension (PAH) (10) and highlighted how sex-based differences play a role in the development and progression of the disease. PAH is more prevalent in women, likely due to the influence of sex hormones (11, 12). Dr. Yamamura’s RNA-seq analysis identified key signaling pathways, such as the Hippo pathway (13), which may contribute to these differences, suggesting that sex-specific therapies could improve PAH outcomes. The involvement of the Hippo pathway aligns with her previous findings on the upregulation of the Ca²⁺-sensing receptor (CaSR) (14) and platelet-derived growth factor (PDGF) receptor (15) expressions. Her work emphasized the necessity of recognizing biological differences, such as sex, when developing treatment strategies.

Dietary Components for Vascular Health: Dr. Katsuko Kajiya’s research explored the effects of Sakurajima Daikon, a Japanese radish, on vascular health (16, 17). Her study demonstrated that this radish can enhance nitric oxide (NO) production in endothelial cells, improving vascular function. A strong candidate of the acting component she identified is trigonelline, a known plant hormone regulating oxidative stress (17). This research provides evidence that food-based interventions may play a role in preventing vascular diseases by enhancing smooth muscle function. Her research illustrated how food components, such as Sakurajima Daikon (also known as “monster radish”) can have a profound effect on smooth muscle function, particularly in vascular health. Furthermore, Dr. Kajiya actively informed local companies about the health benefits of Sakurajima Daikon, and they responded by promoting it as a key local product beneficial to vascular health. Thus, the findings nurtured new food businesses in the local area and the development of new business models established positive flows keeping the project forward.

Key Themes Emerged from The Symposium

The symposium highlighted several key themes that are shaping the future of translational smooth muscle research. Central to these themes are advances in molecular targeting, personalized medicine, and preventive approaches. These insights not only reflect the current state of the field but also point toward promising future directions in smooth muscle pathology and therapy.

Precision Therapies: The identification and manipulation of new molecular pathways emerged as a key strategy in smooth muscle research. Each presentation demonstrated the importance of understanding specific mechanisms, such as Ca²⁺ signaling, estrogen-related signaling in PAH or microbiome interactions in gut health. Calcium dysregulation is a critical factor in both skeletal and smooth muscle disorders, as we learned from the research on malignant hyperthermia (MH) exemplifying the impact of this pathway. By focusing on the ryanodine receptor, Dr. Yamazawa’s work paves the way for precision therapies that directly target molecular mechanisms responsible for muscle dysfunction. This theme extends beyond MH, as calcium signaling is also vital in smooth muscle health across various organ systems. In addition, the estrogen-Hippo signaling axis was also suggested to involve Ca²⁺ signaling in pulmonary arterial smooth muscle cells. Future research will likely continue to investigate how calcium signaling can be manipulated to develop new treatments for diseases such as pulmonary hypertension and gastrointestinal disorders. The continued identification of molecular pathways like these will guide the development of targeted therapies for smooth muscle-related conditions. These molecular insights provide a foundation for developing precision therapies that can address the root causes of disease. Moving forward, further exploration of these pathways will lead to highly specific and effective treatments, not only for rare disorders like malignant hyperthermia but also for more common conditions such as vascular and gastrointestinal diseases.

Personalized Medicine: The symposium emphasized the growing role of personalized medicine in treating smooth muscle disorders. As such, the intense research on PAH underscored how sex-based differences influence disease progression and treatment outcomes. This highlights that the personalized approaches, which consider individual differences, such as sex, genetics, and microbiome composition, are essential for optimizing therapeutic strategies. Efforts have primarily focused on elucidating common themes within each regulatory circuit in smooth muscle. Moving forward, smooth muscle research must emphasize a deeper understanding of the biological variability and diversity present in the systems (18). This will enable the development of personalized treatment plans that are tailored to the specific needs of each patient. This shift toward more individualized care holds significant promise for improving treatment efficacy and patient outcomes.

Preventive Medicine: Preventive approaches, particularly through diet and microbiome modulation, were highlighted as crucial strategies for maintaining smooth muscle health and preventing disease onset and a recurring theme throughout the symposium. The research on Sakurajima Daikon and the work on probiotics/prebiotics for IBD illustrate how natural compounds and microbiome-modulating organisms can positively affect smooth muscle function. These findings suggest that non-invasive interventions could play a key role in the management and prevention of smooth muscle-related diseases. As research progresses, we can expect a broader investigation into how dietary components and probiotics/prebiotics impact smooth muscle health in various systems, such as the vascular, gastrointestinal, and respiratory systems. For example, dietary fibers of the monster radish may play roles as bioactive prebiotics. In the future, research is likely to focus on expanding the use of these interventions to maintain health and prevent disease, particularly in aging populations and those at risk for chronic smooth muscle-related conditions.

Future Directions in Smooth Muscle Research and Beyond

The 66th Annual Meeting of Japan Society of Smooth Muscle Research provided a platform for groundbreaking research that has the potential to transform the way we understand and treat smooth muscle-related diseases. Precision medicine, informed by a deeper understanding of molecular pathways, will enable the development of more targeted therapies. Continued exploration of calcium signaling and other key mechanisms will provide new opportunities for drug development. Personalized medicine will become more prevalent, with treatments tailored to individual patients’ biological profiles, improving outcomes across a range of smooth muscle-related diseases. In addition, non-invasive and natural interventions will likely become central to managing and preventing smooth muscle dysfunction. As the research into functional foods and probiotics continues to evolve, these interventions will be translated into not only clinics but also business, leading to establishing startups that impact on the local economy. Preventive medicine, particularly in the form of early dietary and probiotic interventions, will play a growing role in maintaining smooth muscle health and preventing disease onset. It is also noteworthy that the key takeaway from the four speakers is that deeper and more precise insights into the molecular basis of underlying mechanisms are the fuel that powers translational research. As smooth muscle research continues to evolve, these insights will guide future studies, ultimately leading to new therapies and preventive strategies that improve patient outcomes.

Funding

Grant support: MEXT/JSPS KAKENHI Grant 23K06339-01, 23H02702-01 (to ME).

Conflicts of Interest

None.