Open AccessImpaired myogenic development, differentiation and function in hESC-derived SMA myoblasts and myotubes
Author(s) -
Nicole Hellbach,
Suzanne Peterson,
Daniel Haehnke,
Aditi Shankar,
Samuel LaBarge,
Cullen G Pivaroff,
Stefanie Saenger,
Carolin Thomas,
Kathleen McCarthy,
Martin Ebeling,
Monica H. Bennett,
Uli Schmidt,
Friedrich Metzger
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0205589
Subject(s) - myogenesis , spinal muscular atrophy , smn1 , sma* , biology , myocyte , microbiology and biotechnology , skeletal muscle , endocrinology , genetics , gene , mathematics , combinatorics
Spinal muscular atrophy (SMA) is a severe genetic disorder that manifests in progressive neuromuscular degeneration. SMA originates from loss-of-function mutations of the SMN1 (Survival of Motor Neuron 1) gene. Recent evidence has implicated peripheral deficits, especially in skeletal muscle, as key contributors to disease progression in SMA. In this study we generated myogenic cells from two SMA-affected human embryonic stem cell (hESC) lines with deletion of SMN1 bearing two copies of the SMN2 gene and recapitulating the molecular phenotype of Type 1 SMA. We characterized myoblasts and myotubes by comparing them to two unaffected, control hESC lines and demonstrate that SMA myoblasts and myotubes showed altered expression of various myogenic markers, which translated into an impaired in vitro myogenic maturation and development process. Additionally, we provide evidence that these SMN1 deficient cells display functional deficits in cholinergic calcium signaling response, glycolysis and oxidative phosphorylation. Our data describe a novel human myogenic SMA model that might be used for interrogating the effect of SMN depletion during skeletal muscle development, and as model to investigate biological mechanisms targeting myogenic differentiation, mitochondrial respiration and calcium signaling processes in SMA muscle cells.