# Identifying the Structural Adaptations that Drive the Mechanically Induced Growth of Skeletal Muscle

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $516,040

## Abstract

Project Summary / Abstract
Mechanical signals play a major role in the regulation of skeletal muscle mass, and the maintenance of muscle
mass contributes significantly to disease prevention and quality of life. Although the link between mechanical
signals and the regulation of muscle mass has been recognized for decades, the mechanisms that control this
process remain ill-defined. For instance, most studies indicate that the mechanically induced growth of skeletal
muscle is driven by an increase in the size of the existing myofibers rather than an increase in the number of
myofibers. Moreover, current models assert that the increase in myofiber size is mediated by an increase in the
balance between the rates of protein synthesis and protein degradation which, in turn, leads to the accumulation
of newly synthesized proteins (NSPs) and the concomitant structural changes that drive the growth response.
For instance, it is well known that an increase in mechanical loading can lead to microstructural changes such
as the radial growth of myofibers. Surprisingly, however, the ultrastructural adaptations that drive these
microstructural changes have not been defined. Indeed, a number of foundationally important questions such as
whether the radial growth of myofibers is driven by an increase in the size and/or the number of myofibrils have
not been answered. Likewise, the location(s) in which NSPs accumulate during mechanically induced growth
(i.e., the sites of growth) are not known. As such, one of the major goals of this project is to fill these gaps in
knowledge. Another major goal is to develop a better understanding of the signaling events that control the
different aspects of mechanically induced growth. For instance, our previous work has established that signaling
through mTORC1 plays a central role in the process via which mechanical stimuli induce the radial growth of
myofibers. However, our preliminary data indicate that the longitudinal growth of myofibers can also make a
substantive contribution to the mechanically induced accretion of muscle mass, yet, unlike radial growth, the
longitudinal growth of myofibers does not appear to require signaling by mTORC1. In other words, our preliminary
data suggest that the radial and longitudinal growth of myofibers are regulated by distinct signaling pathways.
Specifically, we propose that the radial growth of myofibers is driven by a mTORC1-dependent mechanism that
we have coined as the “myofibril expansion cycle”, whereas the longitudinal growth of myofibers is mediated by
a mTORC1-independent mechanism that involves transverse Z-line splitting of sarcomeres at regions called
sphenodes. To test the validity of these hypotheses we will use advanced imaging techniques, various genetic
interventions, two complementary models of mechanical load-induced growth, and our new state-of-the-art
technology that enables us to visualize and quantify (with ≤10 nm resolution) where NSPs accumulate.
Collectively, i...

## Key facts

- **NIH application ID:** 10893546
- **Project number:** 5R01AR082816-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** TROY A HORNBERGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $516,040
- **Award type:** 5
- **Project period:** 2023-07-25 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893546

## Citation

> US National Institutes of Health, RePORTER application 10893546, Identifying the Structural Adaptations that Drive the Mechanically Induced Growth of Skeletal Muscle (5R01AR082816-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893546. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*