# Catestatin and its mimetic pharmacophore TKO-10-18 as potential therapies for age-associated muscle loss and the consequent frailty

> **NIH VA I21** · VA SAN DIEGO HEALTHCARE SYSTEM · 2024 · —

## Abstract

Aging-related diseases and disorders affect public health, society, and economics worldwide. Adults 65 years
and older are the fastest growing segment of the US population. Sarcopenia (the age-related loss of muscle
mass and function) is associated with a high risk of morbidity-disability, decreased quality of life, increased
burden of treatment and caregiving, and increased mortality. No medication is currently available to treat
sarcopenia. Therefore, there is a substantial unmet clinical need for effective treatments of sarcopenia.
The dysfunction of the neuromuscular junction (NMJ) plays a crucial role in the development of sarcopenia,
which is characterized by: (i) decreased acetylcholine (ACh) content and muscarinic ACh receptors (mAChRs)
at the NMJ, (ii) decreased activation of AMP kinase and the consequent decrease in mitochondrial biogenesis,
(iii) increased inflammation, (iv) decreased number and activation of satellite cells, and (v) decreased capillary
density. Chromogranin A (CgA) derived peptide catestatin (CST: hCgA352-372) decreases inflammation,
increases AMPK phosphorylation, increases capillary density, increases muscle ACh content, and increases grip
strength in old WT and CST knockout (CST-KO) mice. Therefore, we hypothesize that CST and CST mimetic
pharmacophore TKO-10-18 will ameliorate sarcopenia by reversing sarcopenic phenotypes.
 We have developed 3 Specific Aims to test and validate our hypotheses: Aim I: Evaluation of in vivo
plasma pharmacokinetics of oral CST and TKO-10-18. This aim will determine standard non-compartmental
pharmacokinetic parameters such as AUC, CL, Vss, T1/2, Cmax, Tmax, Clast, and Tlast. Aim II: CST promotes healthy
rehabilitation by improving muscle strength and function in aging WT mice. In Aim II, we will determine
the following: (i) whole body grip strength after 4 months of treatment of 16-month-old mice with saline, oral CST,
and intraperitoneal CST; (ii) sciatic nerve-induced contractility in situ in gastrocnemius muscle; (iii) ex vivo
contraction of soleus and EDL muscles. Based on the existing literature and preliminary data, we expect CST
and TKO-10-18 to increase grip strength in aging WT and CST-KO mice. Aim III. Mechanisms underlying CST
regulation of functional independence or “active aging” in aging WT mice. In Aim III, we will determine the
following: (i) assessment of inflammation by measuring cytokines/chemokines, (ii) muscle regeneration by
determining expression of IL-33, Pax7, Myf5, MyoD1, Mef2, MyoG, Six1 and Six4 genes, (iii) AMPK
phosphorylation by Western blotting, (iv) mitochondrial biogenesis and mitochondrial health by electron
microscopy, (v) determination ACh by ELISA, (vi) capillary density; and (vi) muscle glycogen content. Based on
the published and preliminary data, we expect that CST and TKO-10-18 will improve grip strength in aging mice
by increasing ACh release, activating AMPK, stimulating mitochondrial biogenesis, activating muscle
regeneration, and increasi...

## Key facts

- **NIH application ID:** 10797943
- **Project number:** 1I21RX004398-01A1
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** SUSHIL K MAHATA
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10797943

## Citation

> US National Institutes of Health, RePORTER application 10797943, Catestatin and its mimetic pharmacophore TKO-10-18 as potential therapies for age-associated muscle loss and the consequent frailty (1I21RX004398-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10797943. Licensed CC0.

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