Meeting your heart health goals often appears to be a complex process. It involves keeping track of multiple parameters, including your blood pressure, cholesterol, diabetic tendencies, blood sugar levels, and much more. One might also need to consider the kind of diet to be followed and its impact on the BMI index.
Despite keeping a strict vigil on all these aspects, one might fail to achieve the desired heart health target. At the same time, on the other side of the spectrum, there could be internal modifications to our body’s constitution that might lead to satisfactory results.
Health sciences are continuously evolving, and a new experiment shows that regulated degradation of damaged cell components may prevent heart failure and nerve diseases. In the coming segment, we will delve deeper into this University of Bonn study.
Mechanisms For The Clearing Of Cellular Wastes: Strength Training Activates Such Mechanisms
The research carried out by a team of researchers from the University of Bonn was received with much enthusiasm after it was published in the latest issue of the journal Current Biology for its findings had the potential to establish new therapies for heart failure and nerve diseases. And however far-fetched it might sound, the results could benefit manned space missions.
The Criticality of the Research and the Role of BAG3 Protein
Role in Heart Health
The criticality of the research lies in identifying the role the protein BAG3 plays in eliminating the damaged components of our body, the muscles, nerves, and high-performance organs whose cellular components are subject to constant wear and tear.
The way BAG3 carries out the elimination process is a curious example of how nuanced our body’s internal functions can get. After identifying the damaged components, BAG3 ensures that they are enclosed by cellular membranes to form an “autophagosome,” like a garbage bag for cellular waste to be collected for later shredding and recycling.
However, the larger significance of the research is that it has identified the way to activate BAG3 in the muscles—and that way is strength training. Knowing how to activate BAG3 is crucial because it helps efficiently bind damaged cell components and promote membrane envelopment, resulting in an active elimination or clearing system. The result is the long-term preservation of muscle tissues.
Source: Rheinische Friedrich-Wilhelms-Universität Bonn
While explaining how crucial the absence of BAG3 could prove, Professor Jörg Höhfeld of the University of Bonn, the lead researcher of the team, had the following to say:
“Impairment of the BAG3 system does indeed cause swiftly progressing muscle weakness in children as well as heart failure—one of the most common causes of death in industrialized Western nations.”
Role in Nerve System Health
However, heart health is only one area that would benefit from the research. In addition, the research has greater implications in the overall domain of health. The BAG3 system can mutate to lead to a disease called Charcot-Marie-Tooth syndrome. Furthermore, the current research around BAG3 has led to a better understanding of the cause of the disease. The Charcot-Marie-Tooth syndrome causes arm and leg nerve fibers to die off. As a result, individuals can become unable to move their hands or feet. The researchers, by delving deeper into the functioning of BAG3, have now demonstrated that certain manifestations of the syndrome cause faulty regulation of BAG3 elimination processes.
And if its roles in heart health and the nervous system are well imagined within the contours of health science, one aspect of BAG3 extends to space science.
Role in Space Science
To understand the space scenario and the intricate role that BAG3 plays in it better, let us start with a quote from Prof. Höhfeld, who says the following:
“BAG3 is activated under mechanical force. But what happens if mechanical stimulation does not take place? In astronauts living in a weightless environment, for example, or immobilized intensive care patients on ventilation?”
The lack of mechanical stimulation in an astronaut’s environment is a cause for worry. Partly because of the non-activation of BAG3, there will be muscle atrophy, the wasting, or thinning of the muscle mass.
Therefore, drugs that activate BAG3 could be the solution in cases where astronauts are experiencing muscle atrophy.
The research lead, Prof. Höhfeld, receives funds from the German Space Agency because the research is relevant to manned space missions. The team is all set to conduct experiments on board the International Space Station.
Other Findings from the BAG3 Research
The research had multidisciplinary implications. We have already seen its involvement in the fields of heart health, the health of our neurological systems, and space science. However, it also has important implications for sports training and physical therapy.
The implications of the research on sports-inspired the involvement of sports physiologists at the German Sport University Cologne and the University of Hildesheim. Professor Sebastian Gehlert could not be more simple in his explanation of what this research meant for sports science when he said:
“We now know what intensity level of strength training it takes to activate the BAG3 system, so we can optimize training programs for top athletes and help physical therapy patients build muscle better.”
Summarily, if we look at the research once again, we would realize that what it achieved was humongous. Researchers worldwide are exploring many new ways of combating heart failure. The identification and understanding of the role BAG3 plays make significant additions to those combat strategies.
According to official numbers published by the World Health Organization, Cardiovascular diseases are the leading cause of death globally. Efforts that meaningfully help fight these diseases are nothing less than aids to improving human longevity. The research also impacts another field of diseases that are no less significant than CVDs: neurological problems.
Data suggests that neurological conditions are now the leading cause of health and disability globally, affecting as many as 3.4 billion people worldwide. The research helps solve an aspect of that larger problem, too. Moreover, it leaves its impression on two other areas that are growing competitive each passing day in their way: space science and sports.
Man’s ambition to conquer outer space requires sending manned missions to space for longer periods. This research shows how to make those missions safer for the people involved. Finally, it contributes to improving the health of sports players —a field that perhaps emotionally binds every person who has ever lived on this planet.
The question that arises from all this is: If BAG3 was this important, what took it so long to achieve this breakthrough? Well, the simple answer is that the scientific community has always been active on BAG3—so much so that apart from a myriad of research findings available in the public domain, there is a BAG3 Research Foundation.
In the next few segments, we will delve deeper into this foundation’s functioning, and a couple of the most important research projects carried out in this space in recent years.
The BAG3 Research Foundation
The research foundation’s stated mission is to “provide help and support for children born with the BAG3 P209L mutation.”
The foundation says that there are about 20 children in the world with the ultra-rare heterozygous BAG3 P209L c.626C>T mutation at present. The mutation leads to an unfamiliar version of severe neuromuscular disorder – myofibrillar myopathy 6 (MFM6).
This disease typically follows a typical course, beginning with the onset of rapidly progressive muscle weakness associated with cardiomyopathy, polyneuropathy, respiratory insufficiency during adolescence, skeletal deformities related to muscle weakness, and a rigid spine in some patients.
Initially, these symptoms manifest by making children tired quickly and causing trouble walking due to contracture of the Achilles’ tendons. As the disease progresses, the second decade of their lives sees them affected the most, where they may require a cardiac transplant, ventilation, and/or a wheelchair due to rapidly deteriorating motor and respiratory systems.
The mission aims to intervene by ultimately developing a therapy that would stop the progression of the disease and restore proper muscle function.
Genetics of BAG3: Game Changing Roadmap in AHA Journal
The November 2023 issue of the Journal of American Heart Association came up with suggestions for precision medicines as they saw a trend of BAG3‐related therapies for heart failure moving from the laboratory to the clinic. Their exact understanding and recommendation of the sort was the following:
“The ability to provide precision medicine will depend in large part on having a thorough understanding of the potential effects of both common and uncommon genetic variants on these target proteins.”
In the following segments of their article, they elaborated on the BAG3 gene, its structure, and its functions in cardiomyocytes, the muscle cells that make up the heart’s cardiac muscle or myocardium. Cardiomyocytes play a vital role in the heart’s rhythmic beating and pumping of blood through the circulatory system. While listing the pathogenesis and clinical presentations of BAG3 genetic variants, the journal article mentioned dilated cardiomyopathy, myocarditis, peripartum cardiomyopathy, oncogenesis, and cancer chemotherapy.
BAG3’s Role in Gynaecological Malignancies
Another study published in Nature detailed the role of BAG3 in gynecological malignancies. The research looked into BAG3 as a member of the BAG family of co-chaperons, a multidomain protein involved in several cellular processes. Specifically, it mentioned the role it plays in controlling apoptosis, autophagy, and cytoskeletal dynamics.
Source: Nature
Similar to the research we cited in the opening of our article, the researchers stressed that BAG3’s expression, which is otherwise negligible in most cells, can be induced by stress stimuli or malignant transformation. The researchers noted the role of BAG3’s expression in gynecological cases such as ovarian, endometrial, and cervical cancers.
In some tumors, BAG3 promoted cell survival and resistance to therapy. BAG3 expression also correlated with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix. The researchers identified the need to investigate BAG3 further to understand the nature of the biochemical and functional interaction it has with HPV or human papillomavirus proteins.
As evident from all the significant research we’ve cited so far, BAG3’s role is spread across a variety of medical and healthcare streams, including cardiology, neurology, oncology, gynecology, and more. This multidomain involvement of BAG3 has inspired many pharmaceutical companies to invest further in BAG3-related therapies. In the concluding segments, we will look into a couple of such companies.
#1. Rocket Pharmaceuticals Inc.
In September 2022, Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) reached a definitive agreement with Renovacor, Inc. (NYSE: RCOR), under which Rocket decided to acquire Renovacor in an all-stock transaction for an implied value of approximately $2.60 per share. The coming together of these two companies had BAG3-related therapies in its focus.
While elaborating on how the synergy between Rocket and Renovacor would be helpful in this regard, the MD and CEO of Rocket, Gaurav Shah, said:
“Building on our success in Danon Disease to date, I am particularly excited to expand our cardiology focus and capabilities and address a clear unmet medical need in BAG3-associated dilated cardiomyopathy. By combining Renovacor’s compelling preclinical work with our joint clinical, regulatory, and CMC expertise, we believe we will be well-positioned to bring the highest impact gene therapy with the best chance for success to these patients most productively and efficiently possible.”
More specifically, the acquisition of Renovator was done keeping in mind the company’s most advanced program, REN-001, an AAV-based gene therapy targeting BAG3-associated dilated cardiomyopathy (DCM), a severe form of heart failure. The association with Renovacor helped Rocket access its precision therapy capabilities that address genetically driven cardiac diseases, its world-class scientific collaborator’s robust intellectual property portfolio, and personnel with expertise in BAG3-DCM.
Rocket registered a net loss of US$245.6 million for the financial year ending December 31, 2023.
#2. Obsidian Therapeutics
Obsidian is doing groundbreaking work to deliver gene editing using an AAV in a way that allows gene therapy to be regulated like a small-molecule drug. Since Renovacor’s pioneering solution in the field of BAG3 gene therapy is also AAV-based, Obsidian’s work can complement Renovacor’s solution in the long run.
Obsidian is working with Vertex Pharmaceuticals to deliver its cytoDRiVE technology that makes regulation possible by enabling the editing nuclease to activate only in the presence of a particular small molecule drug. When the drug leaves a patient’s system, the editing activity stops.
What makes Obsidian stand out is that while other technologies use a kill switch for the therapy to go either on or off, Obsidian makes it possible to empower up- and down-regulation. Resultantly, the Obsidian technology helps carry out off-target editing with longer treatment durability and reduced risk of immunogenicity, creating provisions for drug-like properties in the editing process.
According to the latest data available in April 2024, Obsidian had closed a significantly oversubscribed $160.5 million Series C financing with a top-tier syndicate of life science investors led by new investor Wellington Management.
Concluding Thoughts
Understanding the functioning of BAG3 better would make it possible to manipulate it better. Manipulating it better would have a positive impact on a range of therapeutic fields that involve the heart, nerves, and many more important organs of our body.
Apart from what we’ve seen already, decades of relevant research show that BAG3 plays a critical role in maintaining cardiac homeostasis. Research shows that BAG3 could be crucial in the pathobiology of Ischemia or reperfusion injury. A nonsynonymous mutation in BAG3 can lead to the development of myofibrillar myopathy. It even plays a role in human immunodeficiency virus-associated cardiomyopathy.
Altogether, the power to manipulate BAG3 in precise ways can do wonders. And, to come back to the research we started our discussions with, it is now known to us the intensity of strength training it takes to activate the BAG3 system. While therapy programs would serve the needs of specific treatments related to specific organs, simple and scientifically optimized training programs would benefit a large number of people by helping them build their muscles better. Drugs developed to activate BAG3 would further expand the coverage by making it possible to combat muscle atrophy.
Therefore, the impact of BAG3-related therapies not only pertains to improving the standards of healthy living but also combating many complex diseases that have been threatening us for far too long.
Click here to learn how gene editing is likely to become a $30 billion to $60 billion industry by 2030.