Inclusion body myopathy

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Introduction0:00–0:31

In inclusion body myopathy, “myopathy” refers to muscle disease and “inclusion body” refers to the presence of inclusions, or vacuoles, formed by clumps of protein that collect within the muscle fibers.
There’s a sporadic form, sporadic meaning that it strikes at random, which is the most common and is also called inclusion body myositis - because it causes muscle inflammation.
There’s also a rare hereditary form, that causes no muscle inflammation. Normally, the cells of the immune system are ready to spot and destroy anything foreign that could cause the body harm.

Physiology0:31–2:24

To help with this, most cells in the body have a set of proteins that come together to form a major histocompatibility complex, or MHC, class I proteins which sits on the surface of their cell membrane.
These surface proteins act kind of like a serving platter, presenting molecules from within the cell for the immune system, so that it can have a way of performing ongoing surveillance.
Normally the MHC class I proteins serves up a normal harmless molecule from the cell - a self-antigen, and there’s no response.
But if a cell is invaded by a pathogen like a virus, then viral proteins are served upon on the MHC class I proteins. When these viral antigens are displayed on the cell surface, it sparks an immune response.
Specifically, a type of T-lymphocyte, called a CD8+ T-cell or a cytotoxic T-cell, will bind to the antigen presented by the MHC class I proteins.
If the cytotoxic T-cell binds strongly, than the antigen is recognized as foreign, and the cytotoxic T-cell secretes inflammatory molecules and enzymes - like perforin and granzymes.
Perforin is able to form holes in the infected cell and that allows the granzymes to enter the cell. Once inside, the granzymes induce apoptosis, or programmed cell death - which destroys the cell.
And as if that weren’t enough, the cytotoxic T-cells have a protein called Fas ligand on their surface. Fas ligand binds to a protein called Fas on the surface of the infected cell.
And when these two combine, it triggers a cascade of signaling events inside the target cell that also leads to apoptosis.
So either way - the infected cell is doomed. Okay, now, in sporadic inclusion body myositis there are features of inflammation and degeneration.

Pathology2:24–3:50

The exact mechanism is unclear, but one thought is that the trigger may be a virus that infects and damages myocytes. In response, the muscle cells start to present viral antigens on their MHC class I proteins.
The rough endoplasmic reticulum of the myocytes fill up with these MHC class I proteins, and some begin to misfold. The misfolded proteins begin to aggregate and that causes additional degeneration and destruction of muscle fibers.
Alternatively, sporadic inclusion body myositis may be triggered by an autoimmune process. That’s where T- lymphocytes go rogue, and inappropriately start to attack normal myocytes.
In this scenario, sporadic inclusion body myositis is primarily a degenerative disorder, that leads to cellular dysfunction.
This dysfunction can lead to the endoplasmic reticulum of these myocytes improperly creating and folding proteins - resulting in the accumulation of many misfolded proteins.
By comparison, hereditary inclusion myopathy, is a rare inherited genetic disorder. The exact mechanism is unclear, but it’s thought to be related to decreased sialic acid production which plays a role in muscle function.

Symptoms3:50–4:37

Symptoms of sporadic inclusion body myositis include progressive weakness and wasting of proximal and distal muscles - especially involving the quadriceps, the wrists and fingers, and the muscles that lift the front of the foot.
The weakness may not be symmetrical, and it can cause problems like having difficulty climbing up stairs and manipulating fingers.
In severe cases, the muscles of the pharynx or the esophagus are involved, and that can cause dysphagia, or difficulty swallowing.
Hereditary inclusion body myopathy has very similar symptoms, with a key difference being , instead of the quadriceps muscle, it mainly affects the tibialis anterior in the lower leg, resulting in difficulty walking on heels, and difficulty running.

Diagnosis4:37–5:03

Diagnosis is based on elevated levels of muscle enzymes, like creatinine kinase, which get released in the blood when myocytes are destroyed.
Additionally, electromyography can be used to detect regions of dead muscle cells that cause abnormal electrical signals conduction.
Most importantly, a muscle biopsy can show signs of inflammation along with inclusions or vacuoles of abnormal proteins.

Treatment5:03–5:15

In terms of treatment, management relies heavily on exercise and physical therapy, because anti-inflammatory or immunosuppressive drugs aren’t particularly effective.
All right, as a quick recap, inclusion body myopathies are a group of muscle diseases characterized by the presence of abnormal protein inclusions within muscle fibers.

Review5:15–6:37

They most commonly occur sporadically, arising from both inflammatory and degenerative changes, and rarely this result from inherited gene mutations.