Synemin acts as a regulator of signalling molecules in skeletal muscle hypertrophy

Abstract

Synemin, a type IV intermediate filament (IF) protein, forms a bridge between IFs and cellular membranes. As an A-kinase-anchoring protein, it also provides temporal and spatial targeting of protein kinase A (PKA). However, little is known about its functional roles in either process. To better understand its functions in muscle tissue, we generated synemin-deficient (Synm 2/2 ) mice. Synm 2/2 mice displayed normal development and fertility but showed a mild degeneration and regeneration phenotype in myofibres and defects in sarcolemma membranes. Following mechanical overload, Synm 2/2 mice muscles showed a higher hypertrophic capacity with increased maximal force and fatigue resistance compared with control mice. At the molecular level, increased remodelling capacity was accompanied by decreased myostatin (also known as GDF8) and atrogin (also known as FBXO32) expression, and increased follistatin expression. Furthermore, the activity of muscle-mass control molecules (the PKA RIIa subunit, p70S6K and CREB1) was increased in mutant mice. Finally, analysis of muscle satellite cell behaviour suggested that the absence of synemin could affect the balance between self-renewal and differentiation of these cells. Taken together, our results show that synemin is necessary to maintain membrane integrity and regulates signalling molecules during muscle hypertrophy.

Overview of the Muscle Cytoskeleton

“…3). Synemin also plays a role in regulating hypertrophic signaling via interaction with protein kinase A (377). While the interaction of desmin with other intermediate filament proteins are necessary to maintain proper function within the cell, further research needs to be done to better elucidate the molecular role of these interactions in disease.…”

The sarcomeric cytoskeleton: from molecules to motion

“…Connections to the network formed by the IF protein desmin that surrounds the myofibrils (Granger and Lazarides, 1979) can be made by nebulin (Tonino et al, 2010), which, together with another IF, synemin, contributes to the linkage between costameres and the contractile apparatus (García-Pelagio et al, 2015;Li et al, 2014). Further cytoskeletal protein links at the Z-disk periphery exist via the actin crosslinker filamin-C (van der Ven et al, 2000), the actin-IF-tubulin crosslinker plectin (Castañóon et al, 2013), spectrin and the spectrin-like protein nesprin Chapman et al, 2014).…”

Absence of synemin in mice causes structural and functional abnormalities in heart

“…Unlike desmin and the keratins, synemin is a large IF protein that can be expressed in two isoforms, α and β, and requires other IF proteins such as desmin to form heterofilaments [19]. We and others have previously reported that the absence of synemin in murine skeletal muscle is associated with a modest myopathy [25,35]. We also recently showed that the absence of synemin causes osteopenia in skeletal tissue [36].…”