Mechanotransduction: How muscle contraction strengthens tendons

  1. Nicole O Glenn  Is a corresponding author
  2. Clarissa A Henry  Is a corresponding author
  1. St. Jude Children's Research Hospital, United States
  2. University of Maine, United States

Abstract

The force generated by muscles leads to signaling that helps to shape nearby tendon precursor cells.

Main text

The Chinese classic text Tao Te Ching states that “A journey of a thousand miles begins with a single step”. However, this famous proverb does not consider the impact of these steps on the unsung heroes of the musculoskeletal system – the tendons that connect muscle to bones and enable the skeleton to move. Tendon injuries (such as tendonitis, tendinopathy, and tendon rupture) are painful and difficult to heal. Typically caused by overuse, and especially frequent in weightlifters, such injuries occur because the tendon does not adapt as readily to changes in tension as muscle does.

Tendons are fibrous extracellular matrices (ECMs) composed of collagen, proteoglycans and other glycoproteins. In mature tendons, these ECM proteins are secreted by tendon cells. One reason that tendon injuries heal slowly is that tendons have relatively few of these cells (Lui, 2015). Currently, there are no efficient therapies for tendon injuries because it is not well understood how tendons respond to muscle contractions. Now, in eLife, Thomas Schilling of the University of California, Irvine and colleagues – Arul Subramanian (UC Irvine) as first author, Lauren Kanzaki (UC Irvine), and Jenna Galloway (Massachusetts General Hospital) – demonstrate that developing zebrafish embryos are excellent models for studying how tendons adapt to forces (Subramanian et al., 2018). This is because zebrafish embryos have perfected the art of maintaining functional tendons during dramatic growth of the musculoskeletal system.

Muscles and tendons work as an integrated unit to transmit force to the skeletal system and stabilize joints, and there is clear evidence that they depend on each other to develop correctly. In mice, muscles and tendons develop during the same time period and the formation of tendon progenitor cells depends on the presence of early muscle in mouse embryos (Brent et al., 2005). In zebrafish, disrupting muscle development has detrimental effects on the structure of tendons, and disrupting the tendon results in abnormally long muscle fibers (Hall et al., 2007; Goody et al., 2010).

Little is known about how mechanical force affects tendon development, even though force plays an important role in tendon repair. Subramanian et al. therefore established a way to image how tendon precursor cells (also known as tenocytes) develop. This technique uses transgenic zebrafish in which the regulatory elements for a tenocyte-specific gene called scxa control when the fluorescent protein mCherry is expressed (Schweitzer et al., 2001; Chen and Galloway, 2014).

Subramanian et al. observed that muscle contraction helps to shape the tenocytes (Figure 1). The tenocytes elongate and extend protrusions perpendicular to the muscle cells. Unexpectedly, these protrusions are microtubule-based rather than the actin-based protrusions more frequently observed in cells.

Muscle contraction is required for normal tendon development.

(A) During normal muscle development, contractions increase the amount of extracellular matrix proteins, including collagen (green) and Thrombospondin (red), deposited in the developing tendon. These muscle contractions are also required for normal BMP signaling that prompts tenocytes (tendon precursor cells, blue) to elongate and extend complex protrusions (inset panels). (B) In the absence of muscle contraction, extracellular matrix deposition is decreased and tenocytes are rounded with shorter and less complex protrusions.

Immobilized zebrafish embryos developed misaligned tenocytes with shorter and less complex protrusions. The concentration of the tendon ECM protein Thrombospondin, which plays a critical role in tendon development and muscle maintenance (Subramanian and Schilling, 2014), was also disrupted. However, using electrical stimulation to induce muscle contraction in the immobilized zebrafish restored normal tenocyte development and tendon ECM. These creative experiments clearly demonstrate that contractile muscle tissue is required for tendon development.

How do cells integrate mechanical force with biochemical signals? This is a fundamental question throughout cell biology, and Subramanian et al. now have a hypothesis for how this works in tenocytes. They found that contractile force produced by muscle promotes the activity of a signaling pathway called TGFbeta in the tenocytes. Furthermore, TGFbeta is required to form the tenocyte protrusions and to express tenocyte-specific genes, including the gene that produces Thrombospondin. This suggests that one role of the tenocyte protrusions is to secrete and organize the tendon ECM.

The results reported by Subramanian et al. represent a dramatic step forward in our understanding of how tendons respond to contractile force during development. It remains to be seen whether similar mechanisms underlie muscle–tendon dynamics during tendon repair. Could electrical stimulation help tendons to repair themselves? Another major cause of tendon injury is the tendon ECM becoming less elastic with age, leaving one to wonder whether increasing Thrombospondin levels or activating TGFbeta signaling could rescue elasticity. If so, it is worth noting that the UC Irvine team had previously shown that the defects seen in Thrombospondin-deficient zebrafish can be rescued by expressing the human form of the protein (Subramanian and Schilling, 2014). This result indicates that zebrafish and human Thrombospondin work interchangeably, which will allow researchers to use the zebrafish model to investigate the therapeutic potential of this protein.

References

    1. Schweitzer R
    2. Chyung JH
    3. Murtaugh LC
    4. Brent AE
    5. Rosen V
    6. Olson EN
    7. Lassar A
    8. Tabin CJ
    (2001)
    Analysis of the tendon cell fate using scleraxis, a specific marker for tendons and ligaments
    Development 128:3855–3866.

Article and author information

Author details

  1. Nicole O Glenn

    Nicole O Glenn is in the Department of Hematology, St. Jude Children’s Research Hospital, Memphis, United States

    For correspondence
    nikkiollilaglenn@gmail.com
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8890-5506
  2. Clarissa A Henry

    Clarissa Henry is in the School of Biology and Ecology and the Graduate School for Biomedical Sciences and Engineering, University of Maine, Orono, United States

    For correspondence
    Clarissa.Henry@umit.maine.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7204-9231

Publication history

  1. Version of Record published: January 24, 2019 (version 1)

Copyright

© 2019, Glenn and Henry

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,836
    Page views
  • 203
    Downloads
  • 1
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Nicole O Glenn
  2. Clarissa A Henry
(2019)
Mechanotransduction: How muscle contraction strengthens tendons
eLife 8:e44149.
https://doi.org/10.7554/eLife.44149

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Haikel Dridi et al.
    Research Article Updated

    Age-dependent loss of body wall muscle function and impaired locomotion occur within 2 weeks in Caenorhabditis elegans (C. elegans); however, the underlying mechanism has not been fully elucidated. In humans, age-dependent loss of muscle function occurs at about 80 years of age and has been linked to dysfunction of ryanodine receptor (RyR)/intracellular calcium (Ca2+) release channels on the sarcoplasmic reticulum (SR). Mammalian skeletal muscle RyR1 channels undergo age-related remodeling due to oxidative overload, leading to loss of the stabilizing subunit calstabin1 (FKBP12) from the channel macromolecular complex. This destabilizes the closed state of the channel resulting in intracellular Ca2+ leak, reduced muscle function, and impaired exercise capacity. We now show that the C. elegans RyR homolog, UNC-68, exhibits a remarkable degree of evolutionary conservation with mammalian RyR channels and similar age-dependent dysfunction. Like RyR1 in mammals, UNC-68 encodes a protein that comprises a macromolecular complex which includes the calstabin1 homolog FKB-2 and is immunoreactive with antibodies raised against the RyR1 complex. Furthermore, as in aged mammals, UNC-68 is oxidized and depleted of FKB-2 in an age-dependent manner, resulting in ‘leaky’ channels, depleted SR Ca2+ stores, reduced body wall muscle Ca2+ transients, and age-dependent muscle weakness. FKB-2 (ok3007)-deficient worms exhibit reduced exercise capacity. Pharmacologically induced oxidization of UNC-68 and depletion of FKB-2 from the channel independently caused reduced body wall muscle Ca2+ transients. Preventing FKB-2 depletion from the UNC-68 macromolecular complex using the Rycal drug S107 improved muscle Ca2+ transients and function. Taken together, these data suggest that UNC-68 oxidation plays a role in age-dependent loss of muscle function. Remarkably, this age-dependent loss of muscle function induced by oxidative overload, which takes ~2 years in mice and ~80 years in humans, occurs in less than 2–3 weeks in C. elegans, suggesting that reduced antioxidant capacity may contribute to the differences in lifespan among species.

    1. Cell Biology
    Desiree Schatton et al.
    Research Article

    Proliferating cells undergo metabolic changes in synchrony with cell cycle progression and cell division. Mitochondria provide fuel, metabolites, and ATP during different phases of the cell cycle, however it is not completely understood how mitochondrial function and the cell cycle are coordinated. CLUH is a post-transcriptional regulator of mRNAs encoding mitochondrial proteins involved in oxidative phosphorylation and several metabolic pathways. Here, we show a role of CLUH in regulating the expression of astrin, which is involved in metaphase to anaphase progression, centrosome integrity, and mTORC1 inhibition. We find that CLUH binds both the SPAG5 mRNA and its product astrin, and controls the synthesis and the stability of the full-length astrin-1 isoform. We show that CLUH interacts with astrin-1 specifically during interphase. Astrin-depleted cells show mTORC1 hyperactivation and enhanced anabolism. On the other hand, cells lacking CLUH show decreased astrin levels and increased mTORC1 signaling, but cannot sustain anaplerotic and anabolic pathways. In absence of CLUH, cells fail to grow during G1, and progress faster through the cell cycle, indicating dysregulated matching of growth, metabolism and cell cycling. Our data reveal a role of CLUH in coupling growth signaling pathways and mitochondrial metabolism with cell cycle progression.