Characterization of hereditary inclusion body myopathy myoblasts: possible primary impairment of apoptotic events

Abstract

Hereditary inclusion body myopathy (HIBM) is a unique muscular disorder caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. GNE encodes a bi-functional enzyme acting in the biosynthetic pathway of sialic acid. Since the underlying myopathological mechanism leading to the disease phenotype is poorly understood, we have established human myoblasts cultures, derived from HIBM satellite cells carrying the homozygous M712T mutation, and identified cellular and molecular characteristics of these cells. HIBM and control myoblasts showed similar heterogeneous patterns of proliferation and differentiation. Upon apoptosis induction, phosphatidylserine externalization was similar in HIBM and controls. In contrast, the active forms of caspase-3 and -9 were strongly enhanced in most HIBM cultures compared to controls, while pAkt, downregulated in controls, remained high in HIBM cells. These results could indicate impaired apoptotic signaling in HIBM cells. Since satellite cells enable partial regeneration of the post-mitotic muscle tissue, these altered processes could contribute to the muscle mass loss seen in patients. The identification of survival defects in HIBM affected muscle cells could disclose new functions for GNE in muscle cells.

A preclinical trial of sialic acid metabolites on distal myopathy with rimmed vacuoles/ hereditary inclusion body myopathy, a sugar-deficient myopathy: a review

“…Although we and others demonstrated that hyposialylation does exist in DMRV/hIBM cells, others reported that there is no overall hyposialylation in the myoblasts and lymphoblastoid cell line from DMRV/hIBM patients [Salama et al 2005;Hinderlich et al 2004]. In addition, GNE-gene product has been proposed to have functions and roles outside sialic acid biosynthesis [Amsili et al 2007;Wang et al 2006]. We also do not completely discount that there might be other factors that could contribute to the pathogenesis of DMRV/hIBM.…”

Hereditary Inclusion Body Myopathy (HIBM2)

“…The reactivities to lectins are also variable in some myofibers, suggesting that hyposialylation in muscles may contribute to the focal accumulations of autophagic vacuoles and/or amyloid deposits in affected muscle tissue. Although sialic acid dysregulation is likely primary to disease pathogenesis, recent assessments of myoblast cellular sialylation patterns,14,15 suggest the possible role of other GNE-related contributing mechanisms 54,55. Eisenberg et al looked at the role of GNE gene and other neighboring genes, such as, clathrin light chainA (CLTA)56 which is a regulatory element in clathrin gene function, known to be involved in several pathways of lysosomal proteolysis, and, reversion-inducing cysteine-rich protein with Kazal motifs (RECK)57 which is a membrane-anchored glycoprotein with transformation suppressor activity both located close to the GNE gene 58.…”

Preclinical Assessment of wt GNE Gene Plasmid for Management of Hereditary Inclusion Body Myopathy 2 (HIBM2)

“…The sialic acid modifications of cell surface glycoproteins are crucial for cell adhesion and signal transduction and may result in muscle fiber degeneration (Huizing, Hermos et al 2002; Vasconcelos, Raju et al 2002). Although sialic acid dysregulation is likely to significantly contribute to disease pathogenesis, recent assessments of myoblast cellular sialylation patterns suggest the possible role of other GNE related contributing mechanisms, such as GM3 and GD3 synthase regulation and impaired apoptosis signalling (Hinderlich, Salama et al 2004; Salama, Hinderlich et al 2005; Wang, Sun et al 2006; Amsili, Shlomai et al 2007). Additionally, recent developments in the field of GNE research has implicated the bifunctional enzyme to also play a role in functions other than sialic acid production.…”

“…Additionally, recent developments in the field of GNE research has implicated the bifunctional enzyme to also play a role in functions other than sialic acid production. These functions include cell proliferation, apoptosis, regulatory gene expression and modulatory sialytransferases (Wang, Sun et al 2006; Amsili, Shlomai et al 2007). …”