Tenotomy immobilization as a model to investigate skeletal muscle fibrosis (with emphasis on Secreted frizzled-related protein 2)

Abstract

The pathological endpoint of congenital and senile myopathies is chronic muscle degeneration characterized by the atrophy of contractile elements, accompanied by fibrosis and fatty infiltration of the interstitium. Tenotomy is the release of preload that causes abrupt shortening of the muscle and models atrophy and fibrosis without prominent inflammatory response. Fibrosis in the skeletal muscle is known to be triggered by transforming growth factor (TGF)-β, which is activated by inflammatory events. As these were lacking, tenotomy provided an opportunity to investigate transcriptional events on a background without inflammation. An unbiased look at the transcriptome of tenotomy-immobilized soleus muscle revealed that the majority of the transcriptional changes took place in the first 4 wk. Regarding atrophy, proteasomal and lysosomal pathways were actively involved in accompanying cathepsins and calpains in the breakdown of the macromolecular contractile machinery. The transcriptome provided clear-cut evidence for the upregulation of collagens and several extracellular matrix components that define fibrotic remodeling of the skeletal muscle architecture as well as activation of the fibro-adipogenic precursors. Concomitantly, Sfrp2, a Wnt antagonist as well as a procollagen processor, accompanied fibrosis in skeletal muscle with an expression that was stringently confined to the slow-twitch fibers. An interpreted mechanistic scenario construed the kinetic events initiated through the abnormal shortening of the muscle fibers as enough to trigger the resident latent TGF-β in the extracellular matrix, leading to the activation of fibroadipogenic precursors. As in the heart, Sfrp2 shows itself to be a therapeutic target for the prevention of irreversible fibrosis in degenerative skeletal muscle conditions.

PQQ ameliorates skeletal muscle atrophy, mitophagy and fiber type transition induced by denervation via inhibition of the inflammatory signaling pathways

“…It was likely responsible, at least part, for the mechanism by which PQQ alleviated skeletal muscle atrophy, mitigated mitophagy and inhibited slow-to-fast muscle fiber type transition induced by denervation. TGF-β1 could induce skeletal muscle atrophy through activating Smad3, and inactivation of Smad3 could reverse the atrophic effect induced by TGF-β (33,34). The activation of TGF-β signaling pathway is also crucial for autophagy, and it could activate autophagy of human hepatic carcinoma HepG2 cells (68).…”

“…TGF-β1 is a multifunctional cytokine involving in the activation of satellite cells, the formation of connective tissue and the regulation of immune response intensity (32). In skeletal muscle, TGF-β1 could induce skeletal muscle atrophy, requiring Smad3 and JNK activation, and inhibition of Smad3 and JNK1/2 activation could reverse the atrophic effect of TGF-β (33,34). TGF-β1 and p-Smad3 showed significantly increase in murine model of amyotrophic lateral sclerosis, and targeting TGF-β signaling pathway might be a therapeutic approach to improve muscle function in several degenerative diseases (35).…”

Skeletal muscle fibrosis: an overview

“…Tenotomy, resection of muscle tendon, activates interstitial fibrosis (Akpulat et al, 2016, Valencia et al, 2017 due to increased levels of MMP-2, TIMP-2, and TGF-β1 (Hirunsai et al, 2015).…”

“…However, this model lacks myofiber necrosis, inflammatory events, and regenerating myofibers (Akpulat et al, 2016). In addition, tenotomy induces myofiber atrophy which results in loss of the contractile function of muscle (Valencia et al, 2017).…”

Role of Muscle LIM Protein in Mechanotransduction Process

“…The muscle force decrease in reference to the speed of contraction [ 21 ] and the rise of fatigability [ 22 ] has been quantified. Changes have been primarily explained by a global neuromuscular degeneration [ 23 ], atrophy or slow-to-fast fiber switching [ 20 ], sarcomeric or costameric modifications [ 21 , 23 , 24 ], overproduction of no contractile proteins, such as collagen leading to fibrosis [ 25 ], and occasionally apoptosis [ 26 ]. Vernikos and Schneider reported that exposure to microgravity environments can induce neuromuscular atrophy compared to age-induced atrophy, albeit with a possible reversibility [ 2 ].…”