Description of the disease

In the first decade children usually develop normally, but motor coordination and muscle strength are lower than in their peers. Doctors state that everything is on the verge of norm and do not suggest anything particular.

Children, in addition to low strength and endurance, usually have a contracted back muscle (which is manifested by the stiffness of the spine), poor jumping skills, and at some point contractures of the Achilles tendons and walking on toes appear.

Around the age of 10, we can observe a reduced lung capacity, hardening of the calf muscles, damage to the peripheral nerves (peripheral polyneuropathy), and in most cases restrictive cardiomyopathy - a disease that manifests itself by diastolic dysfunction resulting from progressing stiffness of the heart's muscles.

In the following years, all muscles weaken rapidly, causing problems with moving, eating, and finally breathing.

Currently, there are no effective procedures and medicines available to stop the disease. From experience and knowledge exchange, we know that:

• strenuous physical exertion should be strictly avoided

• light physiotherapy is indicated to stretch all muscles

• in the case of strong Achilles tendon contractures, stretching by serial plastering is a very effective method - unlike intense stretching exercises that have the opposite effect. In order to avoid recurrence of contractures, it is necessary to wear orthoses supporting the achieved stretch, every day at least overnight

• one scientific study showed that metformin (a long-known drug for diabetes) restores muscle function in sick zebrafish, but it is difficult to determine whether it also has such effects in humans

• other scientific studies show that inhibition of the preteasome increases disease symptoms, therefore the following should be avoided: capsaicin (chili pepper), turmeric and ibuprofen

• you should also avoid cinnamon, which increases the level of BAG3 protein expression by inducing the HSF1 transcription factor (heat shock factor 1)

A simplified scientific view

Currently, the main problematic site is the formation of protein aggregates during the selective autophagy process performed by the CASA complex (a combination of BAG3, HSP70 and HSPB8 proteins). As a result, mutated BAG3 is trapped in the aggregates and wild BAG3 also sticks to the same aggregates, ultimately drastically reducing the amount of available BAG3 protein. This deficiency disrupts many biological processes, most notably the maintenance of the structure of the Z-Discs, the basic muscle scaffold.

The details of how the mutated protein works are described in the fourth and fifth paragraphs of Article 1 listed below. [link]

Research on BAG3 and the BAG3 P209L mutation

The mutation was discovered more than 10 years ago. So far, a lot of scientific research has been carried out to explain the mechanism of the disease, but none of them has resulted in finding an effective medicine that stops or reverses the disease.

Below are some articles describing various aspects of the BAG3 P209L mutation:

1. Michael Hesse, Bernd K. Fleischmann i inni: Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy

2. A. Schänzer i inni, 2018: Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3

3. Meister-Broekema M, Freilich R, Jagadeesan C, Jason E. Gestwicki, Harm H. Kampinga i inni, 2018: Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks

4. Serena Carrara, Angelo Poletti & Vincenta Timmermana i inni: BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

5. Robert J. Bryson-Richardson: Metformin rescues muscle function in BAG3 myofibrillar myopathy models

6. Igor F. Tsigelny i inni: The role of BAG3 in dilated cardiomyopathy and its association with CharcotMarie-Tooth disease type 2

7. Bernard Brais i inni: BAG3P215L/KO Mice as a Model of BAG3P209L Myofibrillar Myopathy

8. Monte S. Willis i inni: 

• Cardiomyocyte-Specific Human Bcl2-Associated Anthanogene 3 P209L Expression Induces Mitochondrial Fragmentation, Bcl2-Associated Anthanogene 3 Haploinsufficiency, and Activates p38 Signaling

• Discovery of Bag3-P209L signaling mechanism brings hope for therapeutic options currently in development

9. Monte S. Willis i inni: Bag3 P209L myopathies and efficacy of blocking signaling pathways with the therapeutic peptide, MMI-0100

10. Igor F. Tsigelny i inni: New Inhibitors of the P38 Mitogen-Activated Protein Kinase: Repurposing Existing Drugs with Deep Learning

11. Rebecca Robertson, February 2022: BAG3 myofibrillar myopathy: model creation and characterization of a defect in mechanotransduction 

12. Barbara Tedesco, Leen Vendredy, Vincent Timmerman,Angelo Poletti, 03 Jan 2023: The chaperone-assisted selective autophagy complex dynamics and dysfunctions

13. Homma S, Iwasaki M, Shelton GD, et al. Am J Pathol. 2006. Sep;169:761–773: BAG3 Deficiency Results in Fulminant Myopathy and Early Lethality

14. Elisabeth Stürner Christian Behl, June 2017: The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease

15. Heng Lin, Shon A. Koren, Gregor Cvetojevic, Peter Girardi, and Gail V.W. Johnson, May 2021: The Role of BAG3 in Health and Disease: A “Magic BAG of Tricks”

16. Avnika A. Ruparelia, Viola Oorschot, Raquel Vaz, Georg Ramm & Robert J. Bryson-Richardson, 2014: Zebrafish models of BAG3 myofibrillar myopathy suggest a toxic gain of function leading to BAG3 insufficiency

17. Solenn M. Guilbert, Herman Lambert, Marc-Antoine Rodrigue, Margit Fuchs, Jacques Landry, Josée N. Lavoie, 2018: HSPB8 and BAG3 cooperate to promote spatial sequestration of ubiquitinated proteins and coordinate the cellular adaptive response to proteasome insufficiency

18. Thomas G. Martin, Valerie D. Myers, Praveen Dubey, Shubham Dubey, Edith Perez, Christine S. Moravec, Monte S. Willis, Arthur M. Feldman & Jonathan A. Kirk, 2021: Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover