Research Topics: Inclusion Body Myositis (IBM).

Site presented by Bill Tillier

■ Main Page      

■ Overview      

■ Coping      

■ Complications

■ Current Research     

■ Past Research     

■ Autoimmune



Ongoing basic etiological controversy

There has long been controversy over what causes inclusion body myositis. This is somewhat of a "chicken versus the egg" problem. It is clear that there are two components that are primary however, it is not clear if one of these components comes first and causes the other. Sorting this out makes a huge difference because it helps determine the direction of future research and future efforts at developing a treatment. Here is a typical explanation from a recent research publication:

How the inflammatory and degenerative components of the disease are related and whether IBM is a primary autoimmune form of myositis or a degenerative myopathy with inflammatory features remains uncertain and is the subject of ongoing investigation. PubMed Link

Genetic susceptibility

There has been a great deal of research on this topic in the last several years. Research continues to articulate and focus in on the complex genetic relationships to spontaneous inclusion body myositis. Much of this research is being generated by Dr Francis (Frank) Mastaglia in Perth Australia.

For a recent article on this theme see: PubMed Link

Older topics


"The beta amyloid hypothesis: Fundamental questions."

A Central Dogma of IBM research for the past several years has been that beta amyloid abnormalities play a significant role in the disease process. Several recent publications address limitations in the beta-amyloid-mediated hypothesis of IBM myofiber injury, flawed rationales of animal models of this disease, and recent reports regarding potential treatments. Specifically, it appears that the way articles have been referenced has created inaccurate and artificial support for the hypothesis that beta-amyloid is involved in IBM. See Greenberg (2009a), Greenberg, (2009b), Fergusson, 2009 In addition, the sarcoplasmic accumulation of phosphorylated-tau has been hypothesized in the pathology of IBM. Traditionally, this has been assessed using SMI-31 immunoreactivity. This hypothesis has also been recently questioned, see: Salajegheh et al 2009.



Under normal conditions, muscle growth is controlled by a balance between "chemicals" that promote growth versus chemicals that inhibit muscle development. Myostatin is a protein that inhibits muscle growth and normally acts to suppress development to keep muscles within a normal range, otherwise muscle growth could go unchecked. One of the controls of myostatin is another protein called Follistatin. This protein inhibits myostatin -- that is, it blocks the inhibitor, allowing more muscle growth to take place. Researchers are trying to develop ways to inhibit myostatin thus promoting increased muscle growth in people who have various types of muscle diseases. Progress is being made in this area and clinical studies with IBM patients are moving ahead. Although this approach would not be a "cure" for IBM, it might well provide a strategy that would increase the quality of life for IBM patients in the short term.

For more information on this important research see: myostatin . Also please see: PowerPoint presentation


TDP-43 in Sporadic Inclusion Body Myositis

TDP Webpage

PubMed Link

Muscle Nerve. 2009 Jun 16;40(1):8-9. [Epub ahead of print]
Editorial: TDP-43: A reliable immunohistochemistry marker for inclusion body myositis?
Verma A, Tandan R.
Department of Neurology, University of Miami Miller School of Medicine, Clinical Research Building, 1120 NW 14 Street, Suite 1317 Miami, FL 33136.
-TDP-43 is a 414 amino acid protein encoded by the transactive response (TAR) DNA binding protein gene on chromosome 1p36.
-TDP-43 is chiefly involved in well characterized transcription function and RNA splicing regulation. Recent studies suggest that TDP-43 may be involved in other cellular processes, such as microRNA biogenesis, apoptosis, cell division, mRNA stabilization and regulation of neuronal plasticity.
-Over the past year, TDP-43 immunoreactive UBIs have been reported in sIBM and in familial myopathies with or without vacuolar change.
-TDP-43 is so far the most sensitive and specific diagnostic immunohistochemistry marker for IBM.
-to date, no TDP-43 mutation has been associated with sIBM patients.
-It is unknown if protein aggregates are a cause or consequence of the disease process.
Reference: Muscle Nerve. 2009 Jun 16;40(1):19-31. [Epub ahead of print]
Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis.
Salajegheh M, Pinkus JL, Taylor JP, Amato AA, Nazareno R, Baloh RH, Greenberg SA.


Arimoclomol in Sporadic Inclusion Body Myositis

Recent evidence suggests protein misfolding and aggregation play a key role in pathogenesis IBM. Arimoclomol may slow down the process of protein misfolding and aggregation in IBM by helping the muscle fiber to up-regulate inducible heat shock proteins and may slow progression of muscle degeneration.

University of Kansas Medical Center ( Richard Barohn MD ) Clinical Trial found here.


"The Greenberg research group"

Dr. Greenberg is a central figure in IBM research. For a recent article by Dr. Greenberg see: PubMed Link

Dr. Greenberg has posted plans for their NIH IBM research program. These materials can be found here. Further information on IBM can also be found on the associated website found here.


"Lithium Chloride"

It was reported that a recent study found that the common drug lithium chloride (usually used to treat bipolar disorder) may be effective in slowing the development of IBM. The study utilized a mouse model that compared motor function in mice six months after receiving lithium chloride compared to non-treated mice. The data demonstrated that the 'IBM mice' responded significantly to the treatment. The research demonstrated that an enzyme called GSK-3 beta is responsible for increasing the phosphorylation of tau protein, a hallmark of Alzheimer disease. High phospho-tau levels are also seen in IBM. This research demonstrated that lithium chloride blocks the GSK-3 beta enzyme. The impact in a mouse model was to the delay the rate of muscle decline. When this was observed, researchers performed tests on samples of human muscle tissue that confirmed the role of the enzyme again. This research supported the conclusion that clinical trials on IBM patients are indicated and should be conducted immediately.

Reference: Kitazawa M, Trinh DN, Laferla FM (2008). Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase 3 beta. Ann. Neurol. doi:10.1002/ana.21325. PubMed Link

Link to press release (March, 2008)

The underlying rationale of this treatment approach has been questioned by the following article:

PubMed Link

Muscle Nerve. 2009 Jul 22. [Epub ahead of print] [Muscle Nerve. 2009 Jul;40(1):19-31.]
Nature of "Tau" immunoreactivity in normal myonuclei and inclusion body myositis.
Salajegheh M, Pinkus JL, Nazareno R, Amato AA, Parker KC, Greenberg SA.

Comments on the press release and the role of lithium in IBM by Greenberg, 2009a, appear below:

Misstatements to Patients and the Public

Ultimately, the greatest value of scientific research to society is its ability to improve the care of patients. The manner in which scientific findings are conveyed to the public is thus relevant. The University of California at Irvine posted a press release on March, 18, 2008, about the study in which mice were treated with lithium [67]. The press release reported that 'a new UC Irvine study finds that lithium chloride, a drug used to treat bipolar disorder, can slow the development of inclusion body myositis'[68]. No patients with IBM were given lithium; rather, the press release reflects incorrect thinking in which animal experimentation is equated with human disease rather than viewed only as a model for it. This press release further reported that 'mice genetically engineered to have IBM demonstrated markedly better motor function six months after receiving daily doses of lithium chloride, compared with non-treated mice.' In fact, the results reported in the peer-reviewed publication of this study showed no statistically significant difference in motor function in 6-month treated mice. Even though no patient with IBM has ever been reported with the genetic mutations present in these mice or received injections of lipopolysaccharide, and even though the peer-reviewed article did not show any statistically significant treatment effect of lithium in these mice, the principal investigator was quoted in the press release as stating that 'a clinical trial that tests the effectiveness of lithium chloride on IBM patients should be conducted as soon as possible.'