Inclusion Body Myositis


Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in the elderly that results in severe disability. Although traditionally considered an inflammatory myopathy, it is now considered to be more consistent with a myodegenerative disease (Sugarman et al., 2002; Askanas and Engel, 2006).

Clinical Features

The vast majority of IBM occurs sporadically; however, rare familial occurrence has been reported. Inclusion body myositis is a slowly progressive inflammatory myopathy characterized clinically by weakness of the proximal parts of the limbs, diminished deep tendon reflexes, dysphagia, and mixed myopathic and neurogenic changes on electromyography. Baumbach et al. (1990) reported the first familial cases. Six persons in 2 generations were affected in an autosomal dominant pattern of inheritance. All 5 affected males had significant clinical findings with age of onset at 20 to 30 years. The only affected female was clinically asymptomatic but on muscle biopsy showed mild changes consistent with IBM. Garlepp et al. (1995) found particularly severe involvement of the quadriceps femoris muscles in the lower extremity and of the forearm flexor muscles in the upper limbs.

Pathologic Findings

Garlepp et al. (1995) defined IBM histologically by the presence of characteristic rimmed vacuoles with immunohistochemical evidence of the beta-amyloid fragment of the beta-amyloid precursor protein (beta-APP; 104760) and ubiquitin (see UBB; 191339).

Askanas et al. (2003) reported a 70-year-old African American man with sporadic IBM and cardiac amyloidosis associated with a mutation in the transthyretin gene (TTR; 176300.0009). Cultured skeletal muscle fibers from the patient showed vacuolar degeneration, congophilic inclusions, and clusters of colocalizing beta-amyloid and TTR immunoreactivities, none of which were found in normal cultured muscle fibers. Overexpression of the APP gene resulted in accelerated fiber degeneration, greater congophilic inclusions, and accumulation of heavy beta-amyloid oligomers. Askanas et al. (2003) suggested that the TTR mutation may have predisposed the patient to IBM by increasing beta-amyloid deposition in skeletal muscle.

Fratta et al. (2004) found that 70 to 80% of the vacuolated muscle fibers in samples from 10 patients with sporadic inclusion body myositis contained strong immunoreactivity to mutant ubiquitin (UBB+1) in the form of numerous well-defined plaque-like, dotted, or elongated aggregates. Similar aggregates were identified in 10 to 15% of the nonvacuolated normal-appearing fibers. In the abnormal fibers, these aggregates were concurrently immunoreactive for wildtype UBB and either beta-amyloid or phosphorylated tau (MAPT; 157140). None of the control biopsies were immunoreactive to UBB+1. Fratta et al. (2004) suggested that the UBB+1-inhibited proteasome cannot properly degrade toxic proteins, resulting in their accumulation and aggregation.


In a review of the pathogenesis of sporadic IBM, Askanas and Engel (2006) noted the striking similarities to Alzheimer disease (AD; 104300). Muscle fibers and brain tissue from the 2 disorders, respectively, share abnormal protein accumulation, including beta-amyloid, phosphorylated tau, ubiquitin, ApoE (107741), and presenilin-1 (PSEN1; 104311). The authors discussed the abnormalities of APP processing, the role of abnormal intracellular protein folding, oxidative stress, and the potential role of cholesterol in the pathogenic cascade of IBM.

Clinical Management

IBM has traditionally been considered an inflammatory myopathy that has been resistant to treatment, even with immunosuppressive agents. Barohn et al. (2006) reported that 9 IBM patients treated with a TNF-alpha (TNFA; 191160) inhibitor demonstrated a small but significant improvement in handgrip at 12 months. However, other functional measurements did not show improvement.

Molecular Genetics

Garlepp et al. (1995) found the frequency of the apolipoprotein E4 allele to be 0.29 in a group of 14 patients with IBM. This was considerably higher than that found in their control group of other inflammatory diseases (0.15) and the general population (0.13).

Fifteen- to 18-nm tubulofilament inclusions similar to those found in IBM have been observed in some cases of oculopharyngeal dystrophy (164300), which is caused by short expansions of a GCG trinucleotide repeat in the gene encoding poly(A)-binding protein-2 (PABP2; 602279). However, Mezei et al. (1999) did not observe any expansions in PABP2 in 22 sporadic or 3 familial cases of IBM.

Animal Model

Sugarman et al. (2002) noted that affected muscle fibers in IBM are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer disease (104300). Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger beta-APP, seems to be an early pathologic event in both Alzheimer disease and IBM; in the latter, it occurs predominantly intracellularly within affected myofibers. To elucidate the possible role of beta-APP mismetabolism in the pathogenesis of IBM, Sugarman et al. (2002) selectively targeted beta-APP overexpression to skeletal muscle in transgenic mice, using the muscle creatine kinase promoter. They reported that older (more than 10 months) transgenic mice exhibited intracellular immunoreactivity to beta-APP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of beta-APP led to the development of a subset of other histopathologic and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results were considered consistent with a pathogenic role for beta-APP mismetabolism in human IBM.

In a transgenic mouse model of IBM with increased expression of beta-amyloid-42 in skeletal muscle, Kitazawa et al. (2008) observed signs of acute and chronic inflammation after administration of lipopolysaccharide (LPS), as well as exacerbation of motor decline compared to untreated mice. LPS activated glycogen synthase kinase 3-beta (GSK3B; 605004) with concomitantly increased levels of phosphorylated tau and beta-amyloid. Treatment with a specific GSK3B inhibitor or lithium reduced muscle phospho-tau levels and partially rescued motor impairment. Samples of human IBM muscle showed colocalization of GSK3B and phospho-tau. Murine C2C12 myoblasts treated with proinflammatory molecules also showed activated GSK3B and increased tau phosphorylation. Kitazawa et al. (2008) suggested a role for inflammation in IBM and identified GSK3B as a key signaling molecule.