HACD1, a regulator of membrane composition and fluidity, promotes myoblast fusion and skeletal muscle growth

Abstract

The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies, yet the underlying cellular and molecular mechanisms remain elusive. In this study, we investigate the role of HACD1/PTPLA, which is involved in the elongation of the very long chain fatty acids, in muscle fibre formation. In humans and dogs, HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscle weakness. Through analysis of HACD1-deficient Labradors, Hacd1-knockout mice, and Hacd1-deficient myoblasts, we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration. We further demonstrate that in normal differentiating myoblasts, expression of the catalytically active HACD1 isoform, which is encoded by a muscle-enriched splice variant, yields decreased lysophosphatidylcholine content, a potent inhibitor of myoblast fusion, and increased concentrations of ≥C18 and monounsaturated fatty acids of phospholipids. These lipid modifications correlate with a reduction in plasma membrane rigidity. In conclusion, we propose that fusion impairment constitutes a novel, non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism.

The long and short of non-coding RNAs during post-natal growth and differentiation of skeletal muscles: Focus on lncRNA and miRNAs

“…During postnatal growth, the dynamic properties of the sarcolemma are altered to accommodate myoblast fusion (Blondelle et al, 2015), and growing and mature myofibres differ in their response to growth stimuli (Grounds and Shavlakadze, 2011). This is exemplified by the differing effects of IGF on hypertrophic signalling in skeletal muscle depending on the stage of myofibre maturation; IGF1 is a potent stimulator of hypertrophy, but acts mainly on growing muscle, with a lesser effect seen on normal, mature myofibres (Shavlakadze et al, 2010).…”

Alteration of cardiolipin-dependent mitochondrial coupling in muscle protects against obesity

“…In mice and dogs, HACD1 deficiency (Hacd1-KO mice and CNM dogs) leads to reduced muscle mass and strength (Blondelle et al, 2015;Pelé et al, 2005). The hypotrophy arises during postnatal muscle development and remains stable thereafter, whereas the consequences of HACD1 deficiency on muscle function and metabolism remained undeciphered.…”

“…Fatty acids with ≥ C18 acyl chains are synthesized by the very long chain fatty acids (VLCFA) elongation cycle that involves four steps catalyzed by endoplasmic reticulum-resident enzymes (Denic and Weissman, 2007;Ikeda et al, 2008;Kihara, 2012). HACD (3-hydroxyacylCoA dehydratase) proteins catalyze the third step of this elongation cycle and four HACD paralogous genes are present in mammals, with specific expression patterns (Blondelle et al, 2015;Ikeda et al, 2008;Wang et al, 2004). Notably, the full-length isoform of HACD1 (HACD1-fl), which encodes the catalytically active isoform of HACD1, is mainly expressed in striated muscles (Blondelle et al, 2015).…”

“…HACD (3-hydroxyacylCoA dehydratase) proteins catalyze the third step of this elongation cycle and four HACD paralogous genes are present in mammals, with specific expression patterns (Blondelle et al, 2015;Ikeda et al, 2008;Wang et al, 2004). Notably, the full-length isoform of HACD1 (HACD1-fl), which encodes the catalytically active isoform of HACD1, is mainly expressed in striated muscles (Blondelle et al, 2015). We and others identified the essential role of HACD1 in muscle homeostasis through the characterization of loss-of-function mutations in dogs, humans and mice, all leading to congenital myopathies characterized by reduced muscle mass and strength (Blondelle et al, 2015;Muhammad et al, 2013;Pelé et al, 2005;Toscano et al, 2017).…”

“…Notably, the full-length isoform of HACD1 (HACD1-fl), which encodes the catalytically active isoform of HACD1, is mainly expressed in striated muscles (Blondelle et al, 2015). We and others identified the essential role of HACD1 in muscle homeostasis through the characterization of loss-of-function mutations in dogs, humans and mice, all leading to congenital myopathies characterized by reduced muscle mass and strength (Blondelle et al, 2015;Muhammad et al, 2013;Pelé et al, 2005;Toscano et al, 2017). We demonstrated that HACD1 is required for efficient myoblast fusion during muscle postnatal development and as a consequence, HACD1-deficient dogs and mice display an early and uncompensated reduced muscle mass throughout their lifespan (Blondelle et al, 2015).…”