VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy

Abstract

X-linked Myopathy with Excessive Autophagy (XMEA) is a childhood onset disease characterized by progressive vacuolation and atrophy of skeletal muscle. We show that XMEA is caused by hypomorphic alleles of the VMA21 gene, that VMA21 is the diverged human ortholog of the yeast Vma21p protein, and that like Vma21p, VMA21 is an essential assembly chaperone of the vacuolar ATPase (V-ATPase), the principal mammalian proton pump complex. Decreased VMA21 raises lysosomal pH which reduces lysosomal degradative ability and blocks autophagy. This reduces cellular free amino acids which leads to downregulation of the mTORC1 pathway, and consequent increased macroautophagy resulting in proliferation of large and ineffective autolysosomes that engulf sections of cytoplasm, merge, and vacuolate the cell. Our results uncover a novel mechanism of disease, namely macroautophagic overcompensation leading to cell vacuolation and tissue atrophy.

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.…”

Proteasome Dysfunction Induces Muscle Growth Defects And Protein Aggregation

“…Thus, we generated conditional Rpt3-knockout mice to specifically block proteasomal activity in skeletal muscle to clarify the role of the proteasomal system in skeletal muscle tissue. Additionally, because the dysregulation of autophagy is involved in the pathogenic mechanisms of several myopathies, such as Pompe disease (Raben et al, 2008), Danon disease (Nishino et al, 2000), VMA21 deficiency (Ramachandran et al, 2013), autosomal dominant inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia with valosincontaining protein (VCP) mutation (Watts et al, 2004), GNE myopathy (Li et al, 2013) and collagen VI muscular dystrophy (Grumati et al, 2010), we also investigated morphologically similar anomalies using specific immunohistochemical markers of known myopathies in the conditional Rpt3-knockout mice.…”

Fatal hepatic failure and pontine and extrapontine myelinolysis in XMEA

“…Autophagosomal alkalinization impairs autophagy completion, which drives autophagosome proliferation and apparent damage to skeletal muscle. 2 All known XMEA mutations reduce but do not eliminate VMA21 expression. Some cause greater VMA21 reduction than in classic XMEA and lead to a severe course with congenital/neonatal onset, extreme muscle wasting, and ventilation dependence.…”

“…However, even with these mutations, no overt extramuscular disease is present. [2][3][4][5] Given the vital role of V-ATPases in all cells, absence of manifest disease outside muscle is surprising. Possibly, extramuscular pathology is actually present but subclinical.…”