# Protecting the Diabetic Skeletal Muscle by Nampt Activation

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $409,106

## Abstract

Project Summary
Diabetes is a leading cause of death in the US and worldwide with deleterious consequences to the
musculoskeletal system. Regardless of glycemic control, diabetes in skeletal muscle manifests with altered
metabolism leading to progressive skeletal muscle loss, functional decline, fast-type myofiber atrophy,
increased susceptibility to injury and impaired regeneration. The proposal we develop understanding for the
direct causal phenomenon associated with altered metabolism and increased risk to skeletal muscle in
diabetes. We have identified that diabetes causes significant elevation in muscle NADH levels along with
depleted NAD+ reserves. This phenomenon directly associates with decreased muscle function and damage.
Based on our preliminary studies and expertise in the area of pyridine nucleotides and metabolic regulation, we
hypothesize that decreased NAD/NADH ratio in the diabetic skeletal muscle leads to decline in muscle
function, and activation of nicotinamide phosphoribosyl transferase (Nampt) is protective. The major objective
is to develop Nampt activators to protect skeletal muscles from diabetes and other metabolic-related
syndromes. For this, we propose two specific aims. Under Specific Aim 1A, we will rescue insulin resistance in
diabetic skeletal muscle with P7C3. We will utilize diabetic mouse model to identify decreased muscle activity
and strength and the relevance of Nampt, NAD/NADH ratio for improvement of function. The experimental
approach will include functional, biochemical and molecular measurements. These experiments will establish
the fundamental role of NAD/NADH in diabetic skeletal muscle. Specific Aim 1B will develop the innovative
skeletal muscle targeting P7C3 nano particle drug delivery system. The Carnitine-P7C3 particle will allow
higher therapeutic efficacy for in vivo and in vitro delivery. Under Specific Aim 2A we will investigate the
mechanistic basis of P7C3 against diabetic complications in skeletal muscle. The signaling pathway involving
Nampt-HNF1β-PPARα will be elucidated using muscle specific knock out mouse models for HNF1βflox along
with HSAcre mice to evaluate the chief role of hepatocyte nuclear factor 1-β (HNF1β) as a new functional
metabolic modulator in skeletal muscles. Finally, in Sub aim 2B we will investigate the molecular
pharmacology of Nampt and its specificity for targeting and identification of SIRT1, HNF1β along with lipid
signaling mediators involved in muscle protection. Overall, completion of the project will determine the causal
role of Nampt in diabetic skeletal muscle and unravel novel mechanisms with new targets HNF1β that co-
orchestrate with Nampt to optimally regulate metabolism in skeletal muscle.

## Key facts

- **NIH application ID:** 9903303
- **Project number:** 5R01DK119066-02
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Marco Brotto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,106
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9903303

## Citation

> US National Institutes of Health, RePORTER application 9903303, Protecting the Diabetic Skeletal Muscle by Nampt Activation (5R01DK119066-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9903303. Licensed CC0.

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