HSPB7 interacts with dimerized FLNC and its absence results in progressive myopathy in skeletal muscles

Abstract

HSPB7 belongs to the small heat-shock protein (sHSP) family, and its expression is restricted to cardiac and skeletal muscles from embryonic stages to adulthood. Here, we found that skeletal-muscle-specific ablation of the HspB7 does not affect myogenesis during embryonic stages to postnatal day 1 (P1), but causes subsequent postnatal death owing to a respiration defect, with progressive myopathy phenotypes in the diaphragm. Deficiency of HSPB7 in the diaphragm muscle resulted in muscle fibrosis, sarcomere disarray and sarcolemma integrity loss. We identified dimerized filamin C (FLNC) as an interacting partner of HSPB7. Immunofluorescence studies demonstrated that the aggregation and mislocalization of FLNC occurred in the muscle of HspB7 mutant adult mice. Furthermore, the components of dystrophin glycoprotein complex, γ- and δ-sarcoglycan, but not dystrophin, were abnormally upregulated and mislocalized in HSPB7 mutant muscle. Collectively, our findings suggest that HSPB7 is essential for maintaining muscle integrity, which is achieved through its interaction with FLNC, in order to prevent the occurrence and progression of myopathy.

Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy

“…5A), in agreement with Juo et al (2016) who showed that Hspb7 does not contribute directly to myogenesis. Hspb7 has been associated with autophagy but the mechanism is unclear (Vos et al, 2010).…”

“…Hspb7 expression is higher in mdx (a genetic model of muscular dystrophy) mice than in normal mice and is also enhanced in ageing muscle (Doran et al, 2006(Doran et al, , 2007. Recently, a skeletal muscle-specific conditional Hspb7 knockout model was reported to result in progressive myopathy (Juo et al, 2016). The role of Plekhh2 appears to be to stabilize the cortical actin cytoskeleton (Perisic et al, 2012).…”

“…Hspb7 can interact with α-filamin (Krief et al, 1999), filamin C (Juo et al, 2016), the cytoskeleton in tachypaced cardiomyocytes (Ke et al, 2011) and myofibrils in response to cardiac ischemia (Golenhofen et al, 2004). However, based on studies by Vos and colleagues, it appears that Hspb7 could have a role in autophagy and protein degradation, making its role more extensive than previously thought (Vos et al, 2009(Vos et al, , 2010.…”

“…Additionally, the induction of Hspb7 via glucocorticoids could result in a subsequent maladaptive role for Hspb7 if signalling is prolonged. Skeletal muscles deficient in Hspb7 do not show defects in myogenesis but still develop myopathies postnatally, indicating that Hspb7 has a potentially crucial role in skeletal muscle integrity in adults (Juo et al, 2016). It would be interesting to further investigate this in the context of ageing or fasting.…”

“…Hspb7 (also known as cvHsp) is highly expressed in skeletal and cardiac muscle (Krief et al, 1999) and has been linked to cardiac morphogenesis, cardiomyopathies and skeletal muscle integrity in the adult (Chiu et al, 2012;Juo et al, 2016;Rosenfeld et al, 2013). In other cell types, Hspb7 has been shown to prevent protein aggregation (Eenjes et al, 2016;Minoia et al, 2014) and to localize to nuclear speckles (Vos et al, 2009), a sub-nuclear location in which pre-mRNA is spliced.…”