α1-Syntrophin–deficient skeletal muscle exhibits hypertrophy and aberrant formation of neuromuscular junctions during regeneration

Abstract

α1-Syntrophin is a member of the family of dystrophin-associated proteins; it has been shown to recruit neuronal nitric oxide synthase and the water channel aquaporin-4 to the sarcolemma by its PSD-95/SAP-90, Discs-large, ZO-1 homologous domain. To examine the role of α1-syntrophin in muscle regeneration, we injected cardiotoxin into the tibialis anterior muscles of α1-syntrophin–null (α1syn−/−) mice. After the treatment, α1syn−/− muscles displayed remarkable hypertrophy and extensive fiber splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change. In the hypertrophied muscles of the mutant mice, the level of insulin-like growth factor-1 transcripts was highly elevated. Interestingly, in an early stage of the regeneration process, α1syn−/− mice showed remarkably deranged neuromuscular junctions (NMJs), accompanied by impaired ability to exercise. The contractile forces were reduced in α1syn−/− regenerating muscles. Our results suggest that the lack of α1-syntrophin might be responsible in part for the muscle hypertrophy, abnormal synapse formation at NMJs, and reduced force generation during regeneration of dystrophin-deficient muscle, all of which are typically observed in the early stages of Duchenne muscular dystrophy patients.

Reduced proliferative activity of primary POMGnT1-null myoblasts in vitro

“…Western blotting was performed as previously described (Hosaka et al, 2002). In brief, 20 lg of muscle proteins were separated on 7.5% SDS-PAGE gels and transferred to a PVDF membrane (Millipore, Bedford, MA).…”

NO production results in suspension-induced muscle atrophy through dislocation of neuronal NOS

“…eNOS-null muscle revealed atrophy during tail suspension similar to that seen in wildtype muscle (Figure 2, A and B), indicating that eNOS is not essential for atrophy signaling. We previously reported that disruption of the α1-syntrophin gene resulted in dislocation of nNOS from the sarcolemma to the cytoplasm without dystrophic phenotypes (25,26). Suspension of α1-syntrophin-null mice induced severe muscle atrophy as it did in wild-type muscle ( Figure 2, A and B).…”

Eccentric stimulation reveals an involvement of FGF6 in muscle resistance to mechanical stress

“…After a cardiotoxin treatment, muscles from mice lacking a1-syntrophin, another member of the DAPC, displayed remarkable hypertrophy and extensive fibre splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change (Hosaka et al 2002). The lack of a1-syntrophin also might be responsible in part for reduced force generation during regeneration of dystrophin-deficient muscle (Hosaka et al 2002). In another way, Amali et al (2008) reported that overexpression of a new form of myostatin, Mstn2, a member of the TGF-beta superfamily reduces the expression of dystrophin-associated protein complex (DAPC) which leads to muscle dystrophy in zebrafish.…”

“…Dystrophin and proteins of the dystrophin-associated protein complex (DAPC), such as dystroglycan, and sarcoglycan are important for muscle integrity (Grady et al 1997;Collins and Morgan 2003). After a cardiotoxin treatment, muscles from mice lacking a1-syntrophin, another member of the DAPC, displayed remarkable hypertrophy and extensive fibre splitting compared with wild-type regenerating muscles, although the untreated muscles of the mutant mice showed no gross histological change (Hosaka et al 2002). The lack of a1-syntrophin also might be responsible in part for reduced force generation during regeneration of dystrophin-deficient muscle (Hosaka et al 2002).…”