Molecular mechanism of unloading-mediated muscle atrophy and development of its countermeasures

Takeshi Nikawa

doi:10.1186/ar3599

Abstract

The ubiquitin ligase Cbl-b plays a major role in skeletal muscle atrophy induced by unloading [1]. The mechanism of Cbl-b-induced muscle atrophy is unique in that it does not appear to involve the degradation of structural components of the muscle, but rather it impairs muscular trophic signals in response to unloading conditions. Recent studies on the molecular mechanisms of muscle atrophy have focused on the role of IGF-1/PI3K/Akt-1 signaling cascade as a vital pathway in the regulation of the balance between hypertrophy and atrophy [2,3]. These studies indicate that under muscle wasting conditions, such as disuse, diabetes and fasting, decreased IGF-1/PI3K/Akt-1 signaling augments the expression of atrogin-1, resulting in muscle atrophy. However, these studies did not address the mechanisms of unloading-induced impairment of growth factor signaling. In the present study, we found that under both in vitro and in vivo experimental conditions, Cbl-b ubiquitinated and induced specific degradation of IRS-1, a key intermediate of skeletal muscle growth regulated by IGF-1/insulin and growth hormone, resulting in inactivation of Akt-1. Inactivation of Akt-1 led to upregulation of atrogin-1 through dephosphorylation (activation) of FOXO3, as well as reduced mitogen response, in skeletal muscle. Thus, activation of Cbl-b may be an important mechanism underlying the failure of atrophic muscle to respond to growth factor-based treatments such as IGF-1 (Figure (Figure11). Figure 1 Possible mechanism of unloading-mediated muscle atrophy.

Highlights

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Summary

Introduction

Acute isolated neurological syndromes, such as optic neuropathy or transverse myelopathy, may cause diagnostic problems since they can be the first presentations in a number of demyelinating disorders including multiple sclerosis (MS) and collagen diseases. Acute Serum Amyloid A (A-SAA) is an acute phase protein strongly expressed in rheumatoid arthritis (RA) synovial tissue (ST) critically involved in regulating cell migration and angiogenesis These processes are dependent on downstream interactions between extracellular matrix and cytoskeletal components. Conclusions: These results indicate that Egr-1 contributes to IL-1mediated down-regulation of PPARg expression in OA chondrocytes and suggest that this pathway could be a potential target for pharmacologic intervention in the treatment of OA and possibly other arthritic diseases. Immune cell-derived microparticles (MPs) are present at increased amounts in synovial fluid of rheumatoid arthritis (RA) patients [1] and can activate disease-relevant signalling pathways in RA synovial fibroblasts (SF) [2,3].

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