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The compact mutation of myostatin causes a glycolytic shift in the phenotype of fast skeletal muscles.

ABSTRACT: Myostatin is an important negative regulator of skeletal muscle growth. The hypermuscular Compact (Cmpt) mice carry a 12-bp natural mutation in the myostatin propeptide, with additional modifier genes being responsible for the phenotype. Muscle cellularity of the fast-type tibialis anterior (TA) and extensor digitorum longus (EDL) as well as the mixed-type soleus (SOL) muscles of Cmpt and wild-type mice was examined by immunohistochemical staining of the myosin heavy chain (MHC) proteins. In addition, transcript levels of MHC isoforms were quantified by qPCR. Based on our results, all investigated muscles of Cmpt mice were significantly larger compared with that of wild-type mice, as characterized by fiber hyperplasia of different grades. Fiber hypertrophy was not present in TA; however, EDL muscles showed specific IIB fiber hypertrophy while the (I and IIA) fibers of SOL muscles were generally hypertrophied. Both the fast TA and EDL muscles of Cmpt mice contained significantly more glycolytic IIB fibers accompanied by a decreased number of IIX and IIA fibers; however, this was not the case for SOL muscles. In summary, despite the variances found in muscle cellularity between the different myostatin mutant mice, similar glycolytic shifts were observed in Cmpt fast muscles as in muscles from myostatin knockout mice.

SUBMITTER: Baan JA

PROVIDER: S-EPMC3840741 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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The compact mutation of myostatin causes a glycolytic shift in the phenotype of fast skeletal muscles.

Baán Júlia Aliz JA Kocsis Tamás T Keller-Pintér Anikó A Müller Géza G Zádor Ernö E Dux László L Mendler Luca L

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20130826 12

Myostatin is an important negative regulator of skeletal muscle growth. The hypermuscular Compact (Cmpt) mice carry a 12-bp natural mutation in the myostatin propeptide, with additional modifier genes being responsible for the phenotype. Muscle cellularity of the fast-type tibialis anterior (TA) and extensor digitorum longus (EDL) as well as the mixed-type soleus (SOL) muscles of Cmpt and wild-type mice was examined by immunohistochemical staining of the myosin heavy chain (MHC) proteins. In add ...[more]

PMID: 23979839

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Project description:BackgroundMicroRNAs (miRNAs) are a type of non-coding small RNA ~22 nucleotides in length that regulate the expression of protein coding genes at the post-transcriptional level. Glycolytic and oxidative myofibers, the two main types of skeletal muscles, play important roles in metabolic health as well as in meat quality and production in the pig industry. Previous expression profile studies of different skeletal muscle types have focused on these aspects of mRNA and proteins; nonetheless, an explanation of the miRNA transcriptome differences between these two distinct muscles types is long overdue.ResultsHerein, we present a comprehensive analysis of miRNA expression profiling between the porcine longissimus doris muscle (LDM) and psoas major muscle (PMM) using a deep sequencing approach. We generated a total of 16.62 M (LDM) and 18.46 M (PMM) counts, which produced 15.22 M and 17.52 M mappable sequences, respectively, and identified 114 conserved miRNAs and 89 novel miRNA*s. Of 668 unique miRNAs, 349 (52.25%) were co-expressed, of which 173 showed significant differences (P?<?0.01) between the two muscle types. Muscle-specific miR-1-3p showed high expression levels in both libraries (LDM, 32.01%; PMM, 20.15%), and miRNAs that potentially affect metabolic pathways (such as the miR-133 and -23) showed significant differences between the two libraries, indicating that the two skeletal muscle types shared mainly muscle-specific miRNAs but expressed at distinct levels according to their metabolic needs. In addition, an analysis of the Gene Ontology (GO) terms and KEGG pathway associated with the predicted target genes of the differentially expressed miRNAs revealed that the target protein coding genes of highly expressed miRNAs are mainly involved in skeletal muscle structural development, regeneration, cell cycle progression, and the regulation of cell motility.ConclusionOur study indicates that miRNAs play essential roles in the phenotypic variations observed in different muscle fiber types.

Project description:Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 Gain-of-function mutations as a continuum. A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci. 28, 11079-11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T. Therefore, persistent and resurgent currents are likely to determine whether a mutation in Nav1.7 leads to IEM or PEPD.

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The compact mutation of myostatin causes a glycolytic shift in the phenotype of fast skeletal muscles.

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The compact mutation of myostatin causes a glycolytic shift in the phenotype of fast skeletal muscles.

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