Impaired Autophagy in Sporadic Inclusion-Body Myositis and in Endoplasmic Reticulum Stress-Provoked Cultured Human Muscle Fibers

Abstract

The hallmark pathologies of sporadic inclusion-body myositis (s-IBM) muscle fibers are autophagic vacuoles and accumulation of ubiquitin-positive multiprotein aggregates that contain amyloid-␤ or phosphorylated tau in a ␤-pleated sheet amyloid configuration. Endoplasmic reticulum stress (ERS) and 26S proteasome inhibition, also associated with s-IBM, putatively aggrandize the accumulation of misfolded proteins. However, autophagosomal-lysosomal pathway formation and function, indicated by autophagosome maturation, have not been previously analyzed in this system. Here we studied the autophagosomal-lysosomal pathway using 14 s-IBM and 30 disease control and normal control muscle biopsy samples and our cultured human muscle fibers in a microenvironment modified to resemble aspects of s-IBM pathology. We report for the first time that in s-IBM, lysosomal enzyme activities of cathepsin D and B were decreased 60% (P < 0.01) and 40% (P < 0.05), respectively. We also detected two indicators of increased autophagosome maturation, the presence of LC3-II and decreased mammalian target of rapamycinmediated phosphorylation of p70S6 kinase. Moreover, in cultured human muscle fibers, ERS induction significantly decreased activities of cathepsins D and B, increased levels of LC3-II, decreased phosphorylation of p70S6 kinase, and decreased expression of VMA21, a chaperone for assembly of lysosomal V-ATPase. We conclude that in s-IBM muscle, decreased lysosomal proteolytic activity might enhance accumulation of misfolded proteins, despite increased maturation of autophagosomes, and that ERS is a possible cause of s-IBM-impaired lysosomal function. Thus, unblocking protein degradation in s-IBM muscle fibers may be a desirable therapeutic strategy.

Increased autophagy accelerates colchicine-induced muscle toxicity

“…30 Interestingly, in the case of IBMPFD, X-linked myopathy with excessive autophagy and sporadic inclusion body myositis, MTORC1 activity is diminished, suggesting enhanced autophagosome formation. 29,31,32 The current study lends further support to a mechanism of disease in which activation of autophagy drives the vacuolar pathology in some myopathies. Statins initiate autophagy in cultured cells.…”

Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy

“…This study also provides additional evidence for the importance of the autophagic response as a proteostatic mechanism in lung proteinopathies as has been shown for other tissues (3,9,10). Autophagy is increased in lung epithelial cells from PiZ mice and humans.…”

“…Furthermore we demonstrate that the accumulation of misfolded ATZ in pneumocytes has cellular consequences consistent with a proteotoxic effect, i.e. activation of autophagy with increased autophagic flux, identical to what occurs in liver cells in ATZ (9) and other cell types affected by proteinopathies (3,10). The increase in lung collagen deposition models the clinicopathological characteristics of several genetic diseases, including surfactant protein C deficiency (4 -6), surfactant protein A deficiency (51), and Hermansky-Pudlak syndrome (7,8).…”

“…Intracellular accumulation of misfolded protein causes hepatic fibrosis in ␣1-antitrypsin deficiency (ATD) 2 (1), skeletal muscle fibrosis in inclusion-body myositis (2), myocardial fibrosis in mouse models of desminopathy (3), and pulmonary fibrosis in surfactant protein C deficiency (4 -6) and Hermansky-Pudlak syndrome (7,8). Second, autophagy appears to be a dominant proteostatic mechanism for mitigating the hepatic fibrosis in ATD (9), muscle fibrosis in inclusionbody myositis (10), and cardiac fibrosis in desminopathy (3).…”

Effects of long-term resistance exercise training on autophagy in rat skeletal muscle of chloroquine-induced sporadic inclusion body myositis

“…The remarkable pathologic features of sIBM present as vacuolated muscle fibers, accumulations of abnormal proteins that are similar to the pathogens of Alzheimer's and Parkinson's diseases in the brain [4][5][6][7]. Although the exact mechanisms of sIBM remain unclear, strong evidence suggests that the primary cause could be endoplasmic reticulum (ER) stress, unfolded protein response, lysosomal inhibition, and dysfunction of protein degradation systems including autophagy [8][9][10]. Unfortunately, sIBM patients do not respond well to pharmacologic treatments.…”