Lack of the serum- and glucocorticoid-inducible kinase SGK1 improves muscle force characteristics and attenuates fibrosis in dystrophic mdx mouse muscle

Abstract

Duchenne muscular dystrophy (DMD) is a human genetic disease characterized by fibrosis and severe muscle weakness. Currently, there is no effective treatment available to prevent progressive fibrosis in skeletal muscles. The serum- and glucocorticoid-inducible kinase SGK1 regulates a variety of physiological functions and participates in fibrosis stimulation. Here, we investigated whether SGK1 influences structure, function and/or fibrosis of the muscles from the mdx mouse, an animal model for DMD. As expected, mdx muscles showed the typical pathological features of muscular dystrophy including fiber size variations, central nuclei of muscle fibers, fibrosis in the diaphragm, and force reduction by 30-50 %. Muscles from sgk1 (-/-) mice were histologically overall intact and specific force was only slightly reduced compared to wild-type muscles. Surprisingly, soleus and diaphragm muscles of mdx/sgk1 (-/-) mice displayed forces close to wild-type levels. Most muscle fibers of the double mutants contained central nuclei, but fibrosis was not observed in any of the tested limb and diaphragm muscles. We conclude that the sole lack of SGK1 in mouse muscle does not lead to pronounced changes in muscle structure and function. However, dystrophin-deficient mdx muscle seems to benefit from SGK1 deficiency. SGK1 appears to be an important enzyme in the process of fibrotic remodeling and subsequent weakness of dystrophin-deficient mouse muscle.

Proteomic profiling of the dystrophin complex and membrane fraction from dystrophic mdx muscle reveals decreases in the cytolinker desmoglein and increases in the extracellular matrix stabilizers biglycan and fibronectin

“…Among the tested subtypes of skeletal muscle, the biglycan increase was most pronounced in the diaphragm muscle. (Tables 3, 4, as well as supplementary Table S1) This result agrees with the previous findings that the diaphragm is preferentially affected in the mdx mouse and the only muscle showing severe fibre wasting and myofibrosis at early stages (Stedman et al 1991;Steinberger et al 2015). Since elevated biglycan levels were previously also established as damage markers (Nastase et al 2012), these proteomic alterations may be useful to establish new biomarker candidates of dystrophinopathy-related myofibrosis (Ohlendieck and Swandulla 2017).…”

Label‐free mass spectrometric analysis of the mdx‐4cv diaphragm identifies the matricellular protein periostin as a potential factor involved in dystrophinopathy‐related fibrosis

“…Recently, the serum‐ and glucocorticoid‐inducible kinase SGK1 was demonstrated to play a central role in the stimulation of muscular dystrophy related fibrosis. Muscles from sgk1 –/– mice showed greatly improved histological features and specific force as compared to dystrophin‐deficient mdx muscle, indicating that SGK1 deficiency is beneficial to the dystrophic phenotype by attenuating fibrotic remodeling . In the future, the altered concentration of periostin in dystrophinopathy and related signaling molecules and regulatory enzymes might be exploitable for improving diagnostic, prognostic, and therapy monitoring approaches in DMD research.…”

Contractile function recovery in severely injured gastrocnemius muscle of rats treated with either oleic or linoleic acid

“…Along with these events, re-innervation, angiogenesis and extracellular matrix remodelling take place in order to promote full recovery of the injured muscle tissue and muscle function (Fukushima et al 2001;Charge & Rudnicki, 2004;Ciciliot & Schiaffino, 2010;Mann et al 2011). Although the underlying mechanisms involved in the regeneration are not completely understood, several key proteins have been described to participate in this process, including striated muscle activator of Rho signalling, serumand glucocorticoid-inducible kinase-1, phosphatase and tensin homologue, the Notch pathway, latent transforming growth factor-β binding protein-4/transforming growth factor-β signalling, and transient receptor potential channel subfamily A1 (Hu et al 2010;Church et al 2014;Lamon et al 2014;Swaggart & McNally, 2014;Steinberger et al 2015;Osterloh et al 2016;Wallace et al 2016). Severe injuries (e.g.…”