Abstract
CSRP3/MLP (cysteine-rich protein 3/muscle Lim protein), a member of the cysteine-rich protein family, is a muscle-specific LIM-only factor specifically expressed in skeletal muscle. CSRP3 is critical in maintaining the structure and function of normal muscle. To investigate the mechanism of disease in CSRP3 myopathy, we performed siRNA-mediated CSRP3 knockdown in chicken primary myoblasts. CSRP3 silencing resulted in the down-regulation of the expression of myogenic genes and the up-regulation of atrophy-related gene expressions. We found that CSRP3 interacted with LC3 protein to promote the formation of autophagosomes during autophagy. CSRP3-silencing impaired myoblast autophagy, as evidenced by inhibited autophagy-related ATG5 and ATG7 mRNA expression levels, and inhibited LC3II and Beclin-1 protein accumulation. In addition, impaired autophagy in CSRP3-silenced cells resulted in increased sensitivity to apoptosis cell death. CSRP3-silenced cells also showed increased caspase-3 and caspase-9 cleavage. Moreover, apoptosis induced by CSRP3 silencing was alleviated after autophagy activation. Together, these results indicate that CSRP3 promotes the correct formation of autophagosomes through its interaction with LC3 protein, which has an important role in skeletal muscle remodeling and maintenance.
Highlights
Skeletal muscle development and physiology are regulated by many factors and mechanisms
CSRP3 has been reported to be involved in muscle mass and myopathy, the cellular and molecular mechanisms underlying the function of muscle LIM protein (MLP) in regulating muscle myopathy remain unclear
We investigated the effect of CSRP3-KO on atrophy-related genes in skeletal muscle and found that CSRP3-KO significantly increased Atrogin-1 and MuRF-1 mRNA levels and Atrogin-1 protein expression (Figure 1F,G)
Summary
Skeletal muscle development and physiology are regulated by many factors and mechanisms. Evidence has suggested that CSRP3 plays a vital role in skeletal muscle physiology [1,2]. CSRP3, a cytoskeletal protein, is richly expressed in skeletal muscle and cardiac muscle and interacts with telethonin, α-actinin, calcineurin, and cofilin-2, with functions in muscle development and maintenance [3,4,5]. CSRP3 expression levels and intracellular localization are associated with many skeletal myopathies, such as nemaline myopathy, facioscapulohumeral muscular dystrophy (FSHD), and limb-girdle muscular dystrophy type 2B [6,7]. CSRP3 has been reported to be involved in muscle mass and myopathy, the cellular and molecular mechanisms underlying the function of muscle LIM protein (MLP) in regulating muscle myopathy remain unclear
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