# Effects of Osteocyte Factors, WNT3a and PGE2, on Muscle with Aging

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $338,232

## Abstract

ABSTRACT
Sarcopenia is the progressive loss of skeletal muscle mass and force/power that develops with aging.
Accumulating data shows that it is principally the weakness that accompanies sarcopenia, not the loss of muscle
size per se, that contributes to disability. We were the first group to propose that bone cells, specifically
osteocytes, signal to muscle and play an important role in this process. We discovered that soluble factors from
osteocytes from young mice (5 mo) accelerate myogenesis of both C2C12 cells and primary myoblasts, whereas
no effect was observed with factors from osteocytes of aged mice (22 mo). We identified two known osteocyte
factors, PGE2 and Wnt3a (i.e., osteokines), as potential mediators of osteocyte to muscle signaling, as they
closely mimicked the effects of young osteocyte soluble factors on myogenesis. Both Wnt3a and PGE2
significantly upregulated genes that orchestrate growth, hypertrophy, mitochondrial biogenesis, and Ca2+-
release/uptake in muscle. Wnt3a was associated with the translocation of β-catenin to nuclei and was linked to
two downstream genes of the Wnt/β-catenin pathway, Fhl1 and Numb that have direct roles in myogenesis. Our
cell based results were further supported by our ex vivo, in vivo and clinical studies. The conditional deletion of
one allele of β-catenin in osteocytes led to a decrease in both muscle mass and function of skeletal muscles
during aging, while conversely, skeletal muscle function was enhanced in the Lrp5G171V mouse, a model of
increased skeletal Wnt/β-catenin signaling. Clinically, we have found that serum from healthy 60 yr old women,
has high concentrations of WNT3a and increases myogenic differentiation of human primary myoblasts, while
serum from osteoporotic women, which has 1/10 of the WNT3a serum levels of healthy women, decreases
myogenesis. Ex vivo, PGE2 is able to mirror the effects of young osteocyte osteokines by enhancing force
generation in young muscles, but not in aged muscles and the effects were linked to the expression of the EP4
receptor in muscles. Lipidomics profiling revealed that with age, levels of key lipid-signaling mediators of the
arachidonic acid pathway decrease, however exercise rescues the levels of these lipids. These data suggest
that with aging, bone to muscle signaling is defective or muscle response to PGE2 is impaired, potentially through
EP4-PGE2 signaling in aged skeletal muscles. These studies support our hypothesis that bone to muscle
signaling is altered with aging due to compromised Wnt/β-catenin and PGE2 signaling, contributing to
sarcopenia-related muscle weakness. To test this hypothesis, we will conduct the following studies. Aim 1:
Determine the role of Wnt/β-catenin signaling in bone-muscle crosstalk during aging/exercise. Aim 2: Determine
the role of PGE2 signaling in bone-muscle crosstalk during aging/exercise. These studies will provide new
mechanisms for regulation of muscle function by bone-signaling osteokines as well as...

## Key facts

- **NIH application ID:** 9934995
- **Project number:** 5P01AG039355-08
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Marco Brotto
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,232
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934995

## Citation

> US National Institutes of Health, RePORTER application 9934995, Effects of Osteocyte Factors, WNT3a and PGE2, on Muscle with Aging (5P01AG039355-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934995. Licensed CC0.

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