The ubiquitin ligase Cbl-b plays a major role in skeletal muscle atrophy induced by unloading . 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 1).
Figure 1. Possible mechanism of unloading-mediated muscle atrophy.
Nakao R, Hirasaka K, Goto J, Ishidoh K, Yamada C, Ohno A, Okumura Y, Nonaka I, Yasutomo K, Baldwin KM, Kominami E, Higashibata A, Nagano K, Tanaka K, Yasui N, Mills EM, Takeda S, Nikawa T: Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading.
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL: Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy.
Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO, Gonzalez M, Yancopoulos GD, Glass DJ: The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors.