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The mechanisms underlying the cell response to mechanical forces are crucial for muscle development and functionality. We aim to determine whether mutations of the LMNA gene (which encodes lamin A/C) causing congenital muscular dystrophy impair the ability of muscle precursors to sense tissue stiffness and to respond to mechanical challenge. We found that LMNA-mutated myoblasts embedded in soft matrix did not align along the gel axis, whereas control myoblasts did. LMNA-mutated myoblasts were unable to tune their cytoskeletal tension to the tissue stiffness as attested by inappropriate cell-matrix adhesion sites and cytoskeletal tension in soft versus rigid substrates or after mechanical challenge. Importantly, in soft two-dimensional (2D) and/or static three-dimensional (3D) conditions, LMNA-mutated myoblasts showed enhanced activation of the yes-associated protein (YAP) signaling pathway that was paradoxically reduced after cyclic stretch. siRNA-mediated downregulation of YAP reduced adhesion and actin stress fibers in LMNA myoblasts. This is the first demonstration that human myoblasts with LMNA mutations have mechanosensing defects through a YAP-dependent pathway. In addition, our data emphasize the crucial role of biophysical attributes of cellular microenvironment to the response of mechanosensing pathways in LMNA-mutated myoblasts., (© 2014. Published by The Company of Biologists Ltd.)

The aim of the study was to identify daytime predictors of nocturnal gas exchange anomalies in children with neuromuscular disease (NMD) and normal daytime gas exchange. Lung function tests, respiratory muscle evaluation and nocturnal gas exchange were obtained as part of routine evaluation. We included 52 consecutive children with Duchenne muscular dystrophy (n = 20), spinal muscular atrophy (n = 10) and other NMD (n = 22). 20 patients had nocturnal hypoxaemia, defined as minimal arterial oxygen saturation measured by pulse oximetry (S(p,O(2))) <90% for ≥ 2% of night time, and 22 had nocturnal hypercapnia, defined as maximal transcutaneous carbon dioxide tension (P(tc,CO(2))) >50 mmHg for ≥ 2% of night time. Forced vital capacity and helium functional residual capacity correlated with minimal nocturnal S(p,O(2)) (p = 0.009 and p = 0.01, respectively). Daytime pH correlated negatively with maximal nocturnal P(tc,CO(2)) (p=0.005) and daytime arterial carbon dioxide tension (P(a,CO(2))) correlated with the percentage of time with a P(tc,CO(2)) >50 mmHg (p = 0.02). Sniff nasal inspiratory pressure correlated with minimal nocturnal S(p,O(2)) (p = 0.02). Daytime P(a,CO(2)) was a weak predictor of nocturnal hypercapnia (sensitivity 80%; specificity 57%). Daytime lung function and respiratory muscle parameters correlate poorly with nocturnal hypoxaemia and hypercapnia in children with NMD and normal daytime gas exchange, which necessitates more systematic sleep studies in these children.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by motoneuron degeneration in the anterior horn of the spinal cord and in the bulbar nuclei. The various types of SMA are linked to the 5q13 locus in 95 % of cases. In the absence of an effective specific treatment, orthopaedic and respiratory management can significantly improve the prognosis. To study the contemporary natural history of SMA and to identify clinical and non invasive prognostic criteria, 168 patients with SMA were recruited in 6 hospital units (Lille, Lyon, Marseille, Paris) during a 4-year prospective multicenter follow-up study (1998-2002). Follow-up has now lasted at least 4 years in 151 cases (90%), and 24 of these patients have died Disease outcome was appraised by using three criteria: muscle strength, the sum of the motor function and examination index (IFM), the respiratory muscle paralysis index (IMR), and the dorsal decubitus forced vital capacity/theoretical index (ICV/CT). Statistical analysis showed a significant worsening (about 20%) of the three criteria during follow-up. The motor function and examination index (IFM) is particularly interesting: the difference between initial and final status was significant in all age groups and in all three types of the disease. The IFM may thus be useful as the main outcome measure during therapeutic trials.