Macroautophagy as a pathomechanism in sporadic inclusion body myositis.
Skeletal muscle fibers show a high level of constitutive and starvation-induced macroautophagy. Sporadic Inclusion Body Myositis (sIBM) is the most common acquired skeletal muscle disease in patients above the age of 50 years and is characterized by inflammation and intracellular accumulation of aggregate-prone proteins such as amyloid precursor protein (APP)/beta-amyloid, hyperphosphorylated tau, and presenilin. In a recent study, we found that muscle fibers of sIBM patients show increased frequencies of Atg8/LC3(+) autophagosomes and that intracellular APP/beta-amyloid colocalized with Atg8/LC3 in degenerating fibers. Colocalization of APP/beta-amyloid with LC3(+) autophagosomes was further associated with upregulation of major histocompatibility complex (MHC) class I and class II molecules and T cell infiltration. These findings indicate that APP/beta-amyloid is a substrate for autophagy in skeletal muscle fibers and suggest that degradation of aggregate-prone proteins via macroautophagy can be linked with both immune-mediated and degenerative tissue damage. A better understanding of this pathway in skeletal muscle and in the inflammatory environment of sIBM might provide a rationale for novel therapeutic strategies targeting pathogenic protein aggregation.
Lünemann
Jan D
JD
Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, New York 10021, USA.
Schmidt
Jens
J
Dalakas
Marinos C
MC
Münz
Christian
C
D016229:Amyloid beta-Peptides / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000378:metabolism* / Q000473:pathology; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000276:immunology
D016229:Amyloid beta-Peptides; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins