Inclusion Body Myositis: Recent Research and Genetic Links

What is inclusion body myositis?

Inclusion body myositis is a progressive, chronic condition that causes muscle weakness. The muscle weakness slowly progresses and causes difficulties with climbing stairs, walking, lifting things, and swallowing.

Men are three times more likely to have inclusion body myositis than women, and symptoms often begin in the 50s or early 60s. While a rare condition, it is more commonly found in people in Norway, Western Australia,  Minnesota (US), and Japan.[ref]

Sporadic inclusion body myositis:

Inclusion body myositis (IBM) is an inflammatory myopathy, which means it is a disorder that causes inflammation in the muscles. (“Myo” = muscles; “itis” = inflammation)[ref]

The term ‘sporadic’ here means it arises randomly or due to a currently unknown cause. This differentiates the later in life form of inclusion body myositis from the inherited form that tends to occur earlier in life. (More on the inherited form below.)

The main initial symptoms of inclusion body myositis are weakness in the fingers and wrists and weakness in the quadriceps and ankles. Initial diagnosis can be difficult and often misdiagnosed as arthritis or polymyositis.[ref] Additionally, muscles involving swallowing and facial movement can be impacted.[ref]

Muscle tissue changes in inclusion body myositis:

Biopsies of the muscles impacted by IBM show inflammation surrounding the muscle fibers. The muscle fibers are invaded by macrophages and T cells. Additionally, there can be mitochondrial changes in the muscle fibers as well as atrophic fibers.[ref]

Another hallmark of IBM is the formation of rimmed vacuoles and the accumulation of misfolded proteins. This points to an increase in the autophagy pathways.[ref]

This image from a good overview of IBM shows the changes in the muscle tissue (creative commons license):

Misfolded proteins:

Similar to age-related neurodegenerative diseases, the muscle tissue in people with IBM shows an accumulation of amyloid-beta protein, tau tangles, and alpha-synuclein. These proteins are ‘myotoxic‘ in the muscle tissue. When accumulating in the brain, these proteins cause Alzheimer’s and Parkinson’s diseases.[ref]

Increased autophagy:

Autophagy is the way that the body breaks down and recycles different components in the cell. It is often likened to taking out the trash and recycling. The overexpression of proteins associated with autophagy is found in muscle biopsies of sporadic inclusion body myositis.[ref]

In addition to recycling and removing misfolded proteins, defective mitochondria also break down via autophagy. Research is still ongoing as to how and why autophagy is disordered in IBM.

Autoimmune or degenerative disease?

It is not yet clear to researchers whether IBM (inclusion body myositis) is an autoimmune disease – or – if it is a degenerative disease with inflammation.[ref]

One reason that some researchers believe it is an autoimmune disease is that people with IBM often have T cell abnormalities. Genetic research shows that the sporadic form of IBM is associated with known risk factors for autoimmune diseases.[ref]

Bringing this all together:

Like many complex diseases, there is likely not a simple answer to the cause of IBM. Instead, it may be an interplay between inflammation, the dysregulation of proteins, mitochondrial dysfunction, and changes to autophagy. Somewhere in the mix, autoimmunity may be triggering it.

Hereditary form: Inclusion body myopathy 2

Inclusion body myopathy 2 is a genetic form of the disease caused by mutations in the GNE gene. The GNE gene codes for an enzyme essential for creating sialic acid. People with two copies of mutations in the GNE gene can have lower levels of a type of sialic acid needed for the production of certain cell-signaling proteins in muscle cells.[ref][ref]

In comparison to the sporadic form, the familial (genetic) form of the disease can start affecting an individual in early adulthood.

Inflammation is not a big component of the hereditary form of inclusion body myopathy 2. Instead, the muscle biopsies show small fibers as well as protein misfolding.[ref]


Genetics and Inclusion Body Myositis:

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Sporadic Inclusion Body Myositis:

Genetic studies on inclusion body myositis are relatively few. Some of the variants detected have links to autoimmune disorders and others with autophagy.

HLA-DRB1*03:01: this HLA type is associated with a significant increase in risk for inclusion body myositis and other autoimmune disorders

Check your genetic data for rs2187668 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: likely 1 HLA-DRB1*03:01 alleles, increased risk of IBM[ref][ref], as well as other autoimmune disorders
  • T/T: likely 2 HLA-DRB1*03:01 alleles, increased risk of IBM, as well as other autoimmune disorders

Members: Your genotype for rs2187668 is .

 

HLA-B*52: also associated with IBM (SNP not in 23andMe or AncestryDNA)

FYCO1 gene: rare mutations in this gene, which codes for part of the autophagy process, are found in about 11% of people with IBM.[ref] (SNPs not in 23andMe or AncestryDNA)

HMGB1 gene: codes for an important protein in inflammation, especially when triggered by cell death. HMGB1 is upregulated in inclusion body myositis.[ref] I can find no research specifically linking HMGB1 variants to IBM, but if you can check to see if you are likely to have more active HMGB1 in this article: HMGB1 Gene: Inflammatory Response Protein

 

Familial (hereditary) Inclusion Body Myositis:

Note: Genetic data from 23andMe and AncestryDNA is not guaranteed to be 100% clinically accurate. For rare mutations (such as those below), there is a possibility it is a false positive and you should double-check results with a clinical test.

GNE gene: codes for an enzyme needed for making a sialic acid; mutations associated with (familial) inclusion body myopathy 2

Check your genetic data for rs62541771 (23andMe v4, v5):

  • A/A: inclusion body myopathy 2[ref]
  • A/G: carrier of one inclusion body myopathy 2 mutation
  • G/G: typical

Members: Your genotype for rs62541771 is .

Check your genetic data for rs28937594 (23andMe v4, v5; AncestyDNA):

  • A/A: typical
  • A/G: carrier of one inclusion body myopathy 2 mutation
  • G/G: inclusion body myopathy 2 mutation[ref]

Members: Your genotype for rs28937594 is .

VCP gene: codes for a cytosolic protein involved in various cellular activities including mitophagy (autophagy for dysfunctional mitochondria)[ref]

Check your genetic data for rs121909331 A232E (AncestryDNA):

  • G/G: typical
  • G/T: carrier for IBM frontal temporal dementia
  • T/T: pathogenic mutation for myopathies including IBM frontal temporal dementia[ref]

Members: Your genotype for rs121909331 is .

Check your genetic data for rs121909330 R155C (AncestryDNA):

  • G/G: typical
  • G/A: carrier for IBM frontal temporal dementia
  • A/A: pathogenic mutation for myopathies including IBM frontal temporal dementia[ref]

Members: Your genotype for rs121909330 is .

Check your genetic data for rs121909334 R191Q (AncestryDNA):

  • C/C: typical
  • C/T: carrier for IBM frontal temporal dementia
  • T/T: pathogenic mutation for myopathies including IBM frontal temporal dementia[ref]

Members: Your genotype for rs121909334 is .

Check your genetic data for rs121909335 R159H (AncestryDNA):

  • C/C: typical
  • C/T: carrier for IBM frontal temporal dementia
  • T/T: pathogenic mutation for myopathies including IBM frontal temporal dementia[ref]

Members: Your genotype for rs121909335 is .

 


Lifehacks:

If you have inclusion body myositis, talk to your doctor before making any changes to your diet or lifestyle. 

Lifestyle Changes:

Exercise: Several small studies on mild to moderate exercise show that it may help to prevent some of the loss of muscle strength in people with IBM.[ref]

Ketogenic diet: A case study of a 54-year old woman with IBM showed that a low-carb, high-fat ketogenic diet helped to maintain strength, improve walking, and increased quality of life.[ref]

Overall healthy diet: The Myositis Association recommends a ‘healthy diet’ as being important…Their recommendations include avoiding processed food, reducing intake of sugar and flour, and eating vegetables and fish.[ref]  (To me this seems to be an obvious starting point that most people with IBM are likely already doing.)

Supplements for inclusion body myositis:

Boosting NAD+: A recent study (Jan. 2021) showed that increasing NAD+ levels via nicotinamide riboside may help with mitchondrial muscle function. The study used animal models and cell models (not a randomized trial).  [ref]

Mitochondrial supplements: CoQ10 and carnitine may be helpful in reducing symptoms for some individuals.[ref]

Upregulating heat shock proteins: Theoretically, upregulating heat shock proteins may help to promote normal protein folding. Clinical trials for drugs to do this are underway.[ref] Sauna use also upregulates certain heat shock proteins, but I can find no research on it in relation to IBM.

Rapamycin: Trials are underway to see if rapamycin would be beneficial for IBM.[ref]

Keep up with the research:

  • Currently, gene therapy using follistatin is being investigated for its potential muscle-building effects.[ref]
  • Gene therapy is also being investigated for the hereditary form of IBM2.[ref]
  • Stem cells? Animal research shows some promising results for adipose-derived stem cell injections.[ref]
  • Pathway analysis is pointing the way towards new drug trials.[ref]

Related Topics and Articles:

Autophagy genes:

Autophagy is a general term for cellular pathways that move something from the cytoplasm of the cell into the lysosome for degradation.

TNF-alpha and Inflammation:

Tumor necrosis factor (TNF) is an inflammatory cytokine that acts as a signaling molecule in our immune system. In an acute inflammatory situation, TNF-alpha plays an essential role in protecting us, but genetically higher TNF-alpha levels are also linked to chronic inflammatory diseases.

AGEs and RAGEs: 

The receptor for Advanced Glycation Endproducts (RAGEs) is a target for HMGB1

Rapamycin, mTOR, and Your Genes:

Learn about the recent research on rapamycin and how your genetic variants impact mTOR.

 

 




Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.