# Stimulation of Tendon Repair by Metabolic Modifiers

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $349,448

## Abstract

Abstract
Incomplete tendon healing leads to significant mobility restriction, pain and health care cost. While a large
number of clinical and preclinical approaches for drug- and cell-based therapies, rehabilitation and physical
therapy, and other treatment modalities have been attempted, none result in complete recovery of mechanical
structure and function in injured tendons. To address this major clinical problem, it is necessary to define the
molecular changes and mechanisms governing the tendon healing process in order to develop novel targeted
therapies for tendon injury. Interestingly, up-regulation of glycolysis and lactate synthesis occurs in wound,
inflammation, immune response and cancer, and is critical for growth/survival of cancerous tumors and
polarizing of macrophages. Furthermore, substantial evidence demonstrates that these metabolic changes
control growth and differentiation of stem and progenitor cells. These findings support our new concept that
modifying metabolic changes would be an effective therapeutic approach for tissue repair and regeneration.
Recently we determined that IL-1β, which is up-regulated at the tendon injury site, stimulated the expression of
glycolytic enzymes and lactate production in injured-tendon derived progenitors. In addition, once the
progenitors were exposed to IL-1β, they irreversibly reduced the ability to express tenogenic markers and
increased the requirement of lactate synthesis for their proliferation. Our in vivo preliminary data showed that
injured tendons acutely increased an influx of glucose to glyceraldehyde (a metabolite of glycolysis) and lactate.
Furthermore, treatment with the pharmacological inhibitor of lactate synthesis, dichroloacetate (DCA),
decreased the cross-sectional area of injured tendons, stimulated collagen fiber alignment, increased fiber
diameters and dramatically improved the biomechanical properties of injured tendons. Therefore, we have
developed the novel hypothesis that glycolysis and lactate synthesis are up-regulated in tendons after injury
and correction of this alteration directly stimulates tendon healing. The overall objectives of this study are (1) to
determine the metabolic changes during tendon healing and (2) to develop targeted metabolic drugs for tendon
repair. To verify our central hypothesis, we propose three Specific Aims: (1) To establish spatiotemporal
correlations between glucose metabolism in tendons after acute injury and tendon healing; (2) To examine the
effects of glycolysis and lactate synthesis modifiers on tendon healing; and (3) To determine the mechanisms
by which inhibition of lactate synthesis stimulates tendon repair while repressing scar formation. The outcome
of the project will produce a novel link between glucose metabolism and tendon healing, leading to the
development of metabolic modifiers with the ability to promote tendon repair. It will also reveal a novel
mechanism of scar formation involving lactate metabolism.

## Key facts

- **NIH application ID:** 9970417
- **Project number:** 5R01AR070099-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** MOTOMI ENOMOTO-IWAMOTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $349,448
- **Award type:** 5
- **Project period:** 2016-07-12 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970417

## Citation

> US National Institutes of Health, RePORTER application 9970417, Stimulation of Tendon Repair by Metabolic Modifiers (5R01AR070099-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9970417. Licensed CC0.

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