Proteasomes in Distal Myopathy with Rimmed Vacuoles.

Abstract

In a previous report we suggested that muscle fibers in distal myopathywith rimmedvacuoles (DMRV) were degraded by both lysosomal proteolysis (cathepsins) and Ca2+-dependent, nonlysosomal proteolysis (calpain). Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, we examined the role of the ATP-ubiquitin-dependent proteolytic pathway (proteasomes) in myofiber degradation in this myopathy. Immunohistochemically, proteasomes (26S) were located in the cytoplasm in normal human muscle, but the staining intensity was weak. Quantitative analysis showed more reactivity for proteasomes in DMRV muscles and, to a lesser extent, in muscles from muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis patients. In DMRV, proteasomes often were located within or on the rim of rimmedvacuoles, and in the cytoplasm of atrophic fibers. Ubiquitin accumulation was marked within rimmedvacuoles and was seen less extensively in the cytoplasm of atrophic fibers. The latter proteins colocalized well. In other diseased muscles, proteasomes and ubiquitin showed a positive reaction in the atrophic or necrotic fibers. The results indicate increased proteasome and ubiquitin in these muscle fibers as well as in other diseased muscle fibers. Wesuggest that the ATP-ubiquitin-proteasome proteolytic pathway as well as the nonlysosomal calpain and the lysosomal proteolytic pathway may participate in the muscle fiber degradation in DMRV.

Autophagy in a Mouse Model of Distal Myopathy with Rimmed Vacuoles or Hereditary Inclusion Body Myopathy

“…DMRV or hIBM is an early adult-onset autosomal recessive myopathy which usually presents as a gradually progressive myopathy predominantly affecting the distal muscles, 1,2 although proximal muscles can also be affected. On muscle biopsy, a variety of abnormalities is seen, including the characteristic finding of RVs, [3][4][5] intracellular deposition of Congo red-positive materials such as b-amyloid and a-synuclein, 6 abnormal phosphorylation of tau, 7,8 activation of the ubiquitin proteasome system, 9 and activation of the lysosomal system. 10 Until now, however, the precise mechanism that leads to rimmed vacuole formation and/or symptoms in DMRV has remained elusive.…”

Autosomal dominant myopathy: Missense mutation (Glu-706 → Lys) in the myosin heavy chain IIa gene

“…A possible link between rimmed vacuoles and MyHC defects could be that degradation of myosin is, at least partly, mediated by proteasomes (27) and that the ATP-ubiquitin-proteasome proteolytic pathway may participate in muscle fiber degeneration in distal myopathy with rimmed vacuoles (28). Increased degradation of myosin, possibly in addition to other genetic factors and aging, may contribute to the formation of rimmed vacuoles.…”

Role of ubiquitin–proteasome proteolysis in muscle fiber destruction in experimental chloroquine‐induced myopathy

“…Routine histologic analysis was performed using cryostat sections (10-m thick), as described previously. 12,13 Hematoxylin-eosin preparations of each specimen were analyzed with an image analyzer (Cosmozon ISA; Nikon, Tokyo, Japan) attached to a Macintosh computer (Apple, Cupertino, California). The number of fibers with dense granular bodies or vacuoles at the light-microscopic level were determined from 400 muscle fibers per muscle.…”

“…13 Further, immunostaining for cathepsins B and L (lysosomal protease) was increased in denervated muscle from chloroquinetreated rats, suggesting that progression of the degenerative process in this myopathy is mediated by the lysosomal-autophagic process. 13 Because both an autophagic-lysosomal process and a non-lysosomal process (i.e., calpain and ubiquitin-proteasome proteolytic pathways) 15,22 mediate degradation of muscle fibers in denervated muscles, 12 chloroquine-induced dysfunction of the autophagic-lysosome process could represent an excellent mechanistic explanation for vacuole formation. 13 In DMRV and IBM, rimmed vacuoles and some vacuole-free fibers contain abnormally high amounts of ubiquitin, 1,12 which modifies cellular proteins and targets abnormal or normal proteins for highly selective breakdown by an adenosine triphosphate (ATP)-dependent pathway.…”

“…13 Because both an autophagic-lysosomal process and a non-lysosomal process (i.e., calpain and ubiquitin-proteasome proteolytic pathways) 15,22 mediate degradation of muscle fibers in denervated muscles, 12 chloroquine-induced dysfunction of the autophagic-lysosome process could represent an excellent mechanistic explanation for vacuole formation. 13 In DMRV and IBM, rimmed vacuoles and some vacuole-free fibers contain abnormally high amounts of ubiquitin, 1,12 which modifies cellular proteins and targets abnormal or normal proteins for highly selective breakdown by an adenosine triphosphate (ATP)-dependent pathway. 10,16 Recent evidence has indicated that the non-lysosomal ATP-ubiquitin-dependent proteolytic protease, as a multicatalytic protease complex (proteasome), can meditate muscle wasting in the context of various catabolic states.…”