# The Anti-Aging Role of Klotho in Skeletal Muscle Regeneration

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $406,047

## Abstract

ABSTRACT:
 An age-related impairment of the regenerative capacity of aged muscle is a major contributor to
declines in functional mobility and is associated with an increased morbidity in an elderly population. Following
an acute injury, young skeletal muscle initiates a highly effective regenerative response, which largely restores
the original architecture of the damaged fibers. Conversely, with increasing age, the regenerative response to
injury results in a considerable scar tissue deposition at the expense of functional contractile tissue. Much of
this healing defect has been attributed to an age-related decrease in muscle stem, or satellite, cell (MuSC)
functionality. In response to skeletal muscle injury, MuSCs become activated from a quiescent state to repair
damaged myofibers. However, it has been suggested that the increased fibrosis deposition following injury is a
result of a myogenic-to-fibrogenic conversion and cellular senescence of MuSCs. Fortunately, these age-
related changes are reversible. Elegant studies employing heterochronic parabiosis, in which the circulatory
systems of young and aged animals are conjoined, have revealed that rejuvenation of the systemic
microenvironment significantly restores both whole tissue and MuSC regenerative capacity in aged muscle.
These findings implicate that circulating factors, such as Klotho, play a critical role in dictating skeletal muscle
regenerative potential over time. Elucidation of the origin and nature of circulating factors contributing to the
aged muscle phenotype is critical for the development of strategies to prevent, delay or reverse age-related
declines.
 Consistent with the objective of the FOA, the overarching goal of this study is to identify a novel role for
the anti-geronic protein, Klotho, in mediating declines in muscle healing capacity with increasing age, and to
mechanistically test our hypothesis that age-related declines in neuromuscular activity contribute to attenuated
Klotho expression. Specifically, in Aim 1, we will interrogate the underlying mechanism by which Klotho
expression regulates MuSC mitochondrial function and skeletal muscle regenerative potential. In Aim 2, we will
define the molecular mechanisms by which contractile activity stimulates Klotho expression and promotes
muscle healing.
 These studies, when completed, will have a long and lasting impact on the field as they will establish
Klotho as an important anti-geronic factor that regulates MuSC activity essential for functional muscle
regeneration after injury. In addition, these experiments will lay the groundwork for future studies in which
muscle stimulation in geriatric populations may be used to prevent, delay or reverse age-related declines in
muscle function through improved regenerative capacity.

## Key facts

- **NIH application ID:** 9934076
- **Project number:** 5R01AG052978-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Fabrisia Ambrosio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,047
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-09-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934076

## Citation

> US National Institutes of Health, RePORTER application 9934076, The Anti-Aging Role of Klotho in Skeletal Muscle Regeneration (5R01AG052978-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9934076. Licensed CC0.

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