#apaperaday: Mechanisms of Myofibre Death in Muscular Dystrophies: The Emergence of the Regulated Forms of Necrosis in Myology

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Mechanisms of Myofibre Death in Muscular Dystrophies: The Emergence of the Regulated Forms of Necrosis in Myology

Today a review on myofiber death in muscular dystrophies by Bencze in the International Journal of Molecular Sciences. The review contains details on cell death mechanisms and muscle diseases – I’ll give highlights. DOI: 10.3390/ijms24010362

Muscle makes up 30-40% of our body mass dispersed over smaller & larger muscles). It is involved in locomotion, metabolism and e.g. temperature regulation. Muscles are innervated and contract and protected from damage during contraction by dystrophin associated complex (DAPC).

Skeletal muscles consist of long fibers with hundreds or thousands of nuclei. Upon damage muscles can be regenerated by satellite cells. This is a controlled, synchronized process: clear debris, make mold, repair muscle. Inflammatory cells play a role in synchronizing.

In chronic muscle diseases (DAPC not functional as component is missing) there is failed regeneration & loss of muscle. Pathology is characterized by leaky muscles (creatine kinase in blood), reactive oxygen species (oxidative stress), inflammation & loss of Ca2+ homeostasis.

The author stresses that often nomenclature for different processes is used wrong. e.g. dying cells means cells have passed the point of no return – often indicated by caspase 3 markers. However, muscles are fibers, and 1 nucleus dying, may not lead to the whole fiber dying.

Furthermore, caspases are needed for muscle differentiation (last part of repair) so ‘cell death markers’ may not be markers of death but of repair. Author explains different types of cell death: apoptosis (no leakage), necrosis – previously thought to be ‘accidental’.

Recent studies however have shown that necrosis can be regulated (necroptosis – I’d call it plan B, when apoptosis fails because e.g. it is suppressed by a viral infection). Pyroptosis is the process of cell death with leakage and a lot of inflammation. More detail in the image below.

So things are more complex than was thought previously. The author stresses that the processes of necroptosis and pyroptosis are starting to be understood – but likely they are different for multinucleated muscle fibers. So here more research is needed.

Author also mentioned that the heart is even less studied (agreed). Author explains that there is also necrosis initiated by mitochondria – this is currently the target of a number of candidate treatments for muscular dystrophies (‘mitodrugs’).

The bottom line is that more work is needed, but also that researchers should do a better job of terminology (e.g. not calling something cell death when maybe it is not cell death etc). Review gives a nice overview for those with less expertise in cell death processes (aka me).