The ESCRT-0 subcomplex component Hrs/Hgs is a master regulator of myogenesis via modulation of signaling and degradation pathways

Abstract

Background Myogenesis is a highly regulated process ending with the formation of myotubes, the precursors of skeletal muscle fibers. Differentiation of myoblasts into myotubes is controlled by myogenic regulatory factors (MRFs) that act as terminal effectors of signaling cascades involved in the temporal and spatial regulation of muscle development. Such signaling cascades converge and are controlled at the level of intracellular trafficking, but the mechanisms by which myogenesis is regulated by the endosomal machinery and trafficking is largely unexplored. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery composed of four complexes ESCRT-0 to ESCRT-III regulates the biogenesis and trafficking of endosomes as well as the associated signaling and degradation pathways. Here, we investigate its role in regulating myogenesis. Results We uncovered a new function of the ESCRT-0 hepatocyte growth factor-regulated tyrosine kinase substrate Hrs/Hgs component in the regulation of myogenesis. Hrs depletion strongly impairs the differentiation of murine and human myoblasts. In the C2C12 murine myogenic cell line, inhibition of differentiation was attributed to impaired MRF in the early steps of differentiation. This alteration is associated with an upregulation of the MEK/ERK signaling pathway and a downregulation of the Akt2 signaling both leading to the inhibition of differentiation. The myogenic repressors FOXO1 as well as GSK3β were also found to be both activated when Hrs was absent. Inhibition of the MEK/ERK pathway or of GSK3β by the U0126 or azakenpaullone compounds respectively significantly restores the impaired differentiation observed in Hrs-depleted cells. In addition, functional autophagy that is required for myogenesis was also found to be strongly inhibited. Conclusions We show for the first time that Hrs/Hgs is a master regulator that modulates myogenesis at different levels through the control of trafficking, signaling, and degradation pathways.

Exosomal transmission of viruses, a two-edged biological sword

“…In the canonical ESCRT-dependent pathway, ESCRT-0, its HRS domain with tyrosine kinase activity is recruited to the endosomal membrane via phosphatidylinositol-3-Phosphate binding (Fig. 2 A) [ 19 ]. This complex can recognize ubiquitinated proteins and sequestrate into the luminal surface of vesicles [ 19 ].…”

“…2 A) [ 19 ]. This complex can recognize ubiquitinated proteins and sequestrate into the luminal surface of vesicles [ 19 ]. In the latter steps, ESCRT-0, as a member of the sorting machinery system, is recalled followed by the addition of ESCRT-I, -II, and –III [ 20 ].…”

Cancer cachexia: molecular mechanisms and treatment strategies

“…Anabolism is related to protein synthesis and comprises several important pathways, such as the mammalian target of rapamycin (mTOR), insulin and insulin-like growth factor1 (IGF1)-AKT, and bone morphogenetic protein (BMP)/Smad1/5/8. Catabolic pathways are linked to protein degradation, which includes the ubiquitin (Ub)-proteasome system (UPS), cell autophagy/lysosomal pathway (ALP), and Ca 2+ -activated degradation [ 2 , 4 ]. The imbalance between these pathways leads to loss of muscle mass and muscle-wasting conditions.…”

Expression profile and bioinformatics analysis of circRNA and its associated ceRNA networks in longissimus dorsi from Lufeng cattle and Leiqiong cattle

“…However, the growth and development of muscle fibers include ontogeny at different embryonic stages, as well as hypertrophy and transformation at postnatal stages [ 9 , 11 ]. In addition, the process of myogenesis is a complex biological process regulated by multiple factors, such as myogenic regulatory factors [ 12 ], signaling pathways [ 13 ], noncoding RNAs (ncRNAs) [ 14 ], and genes. Among these factors, circular RNA (circRNA) is an ncRNA with a covalently closed continuous loop structure that can play a role in gene regulation by competing with linear splicing [ 15 ], and this factor plays an important regulatory role in myogenesis [ 16 ].…”