Mechanosensitive Molecular Networks Involved in Transducing Resistance Exercise-Signals into Muscle Protein Accretion

Abstract

Loss of skeletal muscle myofibrillar protein with disease and/or inactivity can severely deteriorate muscle strength and function. Strategies to counteract wasting of muscle myofibrillar protein are therefore desirable and invite for considerations on the potential superiority of specific modes of resistance exercise and/or the adequacy of low load resistance exercise regimens as well as underlying mechanisms. In this regard, delineation of the potentially mechanosensitive molecular mechanisms underlying muscle protein synthesis (MPS), may contribute to an understanding on how differentiated resistance exercise can transduce a mechanical signal into stimulation of muscle accretion. Recent findings suggest specific upstream exercise-induced mechano-sensitive myocellular signaling pathways to converge on mammalian target of rapamycin complex 1 (mTORC1), to influence MPS. This may e.g. implicate mechanical activation of signaling through a diacylglycerol kinase (DGKζ)-phosphatidic acid (PA) axis or implicate integrin deformation to signal through a Focal adhesion kinase (FAK)-Tuberous Sclerosis Complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) axis. Moreover, since initiation of translation is reliant on mRNA, it is also relevant to consider potentially mechanosensitive signaling pathways involved in muscle myofibrillar gene transcription and whether some of these pathways converge with those affecting mTORC1 activation for MPS. In this regard, recent findings suggest how mechanical stress may implicate integrin deformation and/or actin dynamics to signal through a Ras homolog gene family member A protein (RhoA)-striated muscle activator of Rho signaling (STARS) axis or implicate deformation of Notch to affect Bone Morphogenetic Protein (BMP) signaling through a small mother of decapentaplegic (Smad) axis.

Interactions between Muscle and Bone—Where Physics Meets Biology

“…However, research is still necessary to unravel the role of Notch signaling both in fate decision and morphogenesis during development and in postnatal muscle regeneration, as evidenced in dystrophic mice [131,134]. Analogous to our findings in skeletal precursors, mechanically induced Notch signaling is involved in a protein network that regulates myostatin expression in the context of cytoskeletal rearrangements via integrin-mediated AKT/PKB and mTORC1 signaling [58,135].…”

Recurrent training rejuvenates and enhances transcriptome and methylome responses in young and older human muscle

“…In striated muscle, vinculin is a structural component of costameres 88 , which connects sarcomeres to the cell membrane to stabilize myofibres during contraction and relaxation. The gene, furthermore, potentiates mechanosensing 89,90 and is upregulated in skeletal muscle tissue following chronic stimulation and disuse 91 . Most interestingly, VCL is part of the focal adhesion pathway, which was enriched during both training, detraining and retraining in older men, as well as during training, immobilization and retraining in younger men and the age-related comparison between young and old.…”

Activation of mTORC1 signalling in rat skeletal muscle is independent of the EC‐coupling sequence but dependent on tension per se in a dose‐response relationship

“…On the contrary, possible mechanosensitive proteins could be located in structural regions of the muscle cell subjected to tensile stress during passive deformation. The most likely candidate proteins include those associated with the sarcolemma (eg, integrins or cadherins), focal adhesion (eg, FAK or actin filaments), costamere (eg, dystrophin and vinculin) and the sarcomeric Z‐line (eg, titin, phospholipase D or Filamin C unfolding‐BAG3) …”

“…The most likely candidate proteins include those associated with the sarcolemma (eg, integrins or cadherins), focal adhesion (eg, FAK or actin filaments), costamere (eg, dystrophin and vinculin) and the sarcomeric Z-line (eg, titin, phospholipase D or Filamin C unfolding-BAG3). 20,[29][30][31][32] Only a few other studies have investigated the effect of T peak on anabolic signalling, while controlling for other tension-related parameters. However, the results from these studies are conflicting.…”

“…Despite identification of potentially mechanosensitive proteins involved in anabolic signalling only circumstantial evidence exists for an effect of the tension exerted on the muscle cell independent of other factors (ie, tension per se) on activation of mTORC1 signalling. In accordance, an important obstacle still remains from previous studies on the effect of different levels of tension development on anabolic signalling, which complicates interpretation.…”