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      Signaling pathways controlling skeletal muscle mass

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          Abstract

          The molecular mechanisms underlying skeletal muscle maintenance involve interplay between multiple signaling pathways. Under normal physiological conditions, a network of interconnected signals serves to control and coordinate hypertrophic and atrophic messages, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed “atrophy”, is a diagnostic feature of cachexia seen in settings of cancer, heart disease, chronic obstructive pulmonary disease, kidney disease, and burns. Cachexia increases the likelihood of death from these already serious diseases. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce differentiation and post-injury regeneration, which are also essential for the maintenance of skeletal muscle mass. In this review, we summarize and discuss the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle.

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          Most cited references97

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          Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.

          Glycogen synthase kinase-3 (GSK3) is implicated in the regulation of several physiological processes, including the control of glycogen and protein synthesis by insulin, modulation of the transcription factors AP-1 and CREB, the specification of cell fate in Drosophila and dorsoventral patterning in Xenopus embryos. GSK3 is inhibited by serine phosphorylation in response to insulin or growth factors and in vitro by either MAP kinase-activated protein (MAPKAP) kinase-1 (also known as p90rsk) or p70 ribosomal S6 kinase (p70S6k). Here we show, however, that agents which prevent the activation of both MAPKAP kinase-1 and p70S6k by insulin in vivo do not block the phosphorylation and inhibition of GSK3. Another insulin-stimulated protein kinase inactivates GSK3 under these conditions, and we demonstrate that it is the product of the proto-oncogene protein kinase B (PKB, also known as Akt/RAC). Like the inhibition of GSK3 (refs 10, 14), the activation of PKB is prevented by inhibitors of phosphatidylinositol (PI) 3-kinase.
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            IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

            Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.
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              Double muscling in cattle due to mutations in the myostatin gene.

              Myostatin (GDF-8) is a member of the transforming growth factor beta superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.
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                Author and article information

                Journal
                Crit Rev Biochem Mol Biol
                Crit. Rev. Biochem. Mol. Biol
                BMG
                Critical Reviews in Biochemistry and Molecular Biology
                Informa Healthcare USA, Inc.
                1040-9238
                1549-7798
                January 2014
                18 November 2013
                : 49
                : 1
                : 59-68
                Affiliations
                Novartis Institutes for Biomedical Research Cambridge, MAUSA
                Author notes
                Address for correspondence: David J. GlassNovartis Institutes for Biomedical Research 100 Technology Square, RM 4210, Cambridge, MA 02139USA. E-mail: david.glass@ 123456novartis.com
                Article
                10.3109/10409238.2013.857291
                3913083
                24237131
                63bcdc8a-5311-43a8-9ea9-335d51d14281
                © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted

                This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.

                History
                : 4 September 2013
                : 16 October 2013
                : 16 October 2013
                Categories
                Review Article

                Molecular biology
                igf-1,muscle hypertrophy,skeletal muscle,murf1,cachexia,sarcopenia,myostatin,muscle atrophy
                Molecular biology
                igf-1, muscle hypertrophy, skeletal muscle, murf1, cachexia, sarcopenia, myostatin, muscle atrophy

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