# Mechanisms of Malnutrition in Cirrhosis with Portosystemic Shunting

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $304,842

## Abstract

There are ~ 2.5 million cirrhotics in United States with over 27,000 deaths annually. Despite liver
transplantation, loss in muscle mass or sarcopenia is the most frequent complication that contributes to
adverse clinical outcomes in cirrhosis. However, there are no established therapies as the underlying
mechanisms of sarcopenia in cirrhosis are not well understood and therefore the proposed studies are of high
clinical significance. In the previous funding cycle, we showed that hyperammonemia (a consistent abnormality
in cirrhosis) results in activation p65NFkB mediated increased expression of myostatin that inhibits muscle
protein synthesis. Since the NFkB-myostatin pathway is activated in response to ammonia, the key question in
the renewal is to address the molecular mechanisms of how ammonia mediates muscle loss. Based on
exciting preliminary data generated by studies in human cirrhotics, rodent models of hyperammonemia, cell
culture studies in myotubes, we hypothesize that hyperammonemia inhibits skeletal muscle protein synthesis
through non-canonical molecular signaling via MyD88 and metabolic stabilization of HIF1α. We plan to address
this hypothesis through following aims: First we will identify the mechanism by which hyperammonemia
activates NFkB. Our preliminary data shows that in response to hyperammonemia, RhBG, an ammonia
transporter interacts with MyD88 (an adaptor protein for toll like receptor pathway). This non-conical interaction
of MyD88 with RhBG activates the downstream signaling response as MyD88 silencing resulted in loss of
NFkB activation despite hyperammonemia. Using muscle-specific conditional knockout mice along with
cellular studies, we will identify the mechanism by which ammonia promotes RhBG-MyD88 interaction leading
to signaling responses that activate NFkB. Second, we will determine how hyperammonemia induced
myostatin inhibits the critical protein synthesis regulatory molecule, mTORC1 via the myostatin receptor
complex (ALK5-ActIIBr). Our preliminary evidence shows that in hyperammonemia, classical AMPK kinases
are not activated and that ALK5 functions as a novel AMPK kinase as depletion of ALK5 by knock down results
in loss of AMPK activation. Studies using conditional muscle specific AMPK knockout mice will be
complemented with cellular studies in myotubes to determine that ActIIBr-ALK5 is a novel AMPK kinase during
hyperammonemia and is responsible for inhibiting protein synthesis. Third, we will dissect how metabolic
disposal of ammonia in the muscle via mitochondrial metabolite, α ketoglutarate (αKG) impairs mTORC1 and
hinders protein synthesis by stabilizing HIF1α. We will use mice with muscle specific HIF1α deletion and αKG
precursors in our hyperammonemic cell culture model for these studies. Studies in this aim are critical to the
idea that the skeletal muscle plays a key role in ammonia detoxification and that metabolic perturbations result
in deleterious effects of hyperammonemia. Our novel, integra...

## Key facts

- **NIH application ID:** 9952384
- **Project number:** 5R01GM119174-09
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Srinivasan Dasarathy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $304,842
- **Award type:** 5
- **Project period:** 2011-08-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9952384

## Citation

> US National Institutes of Health, RePORTER application 9952384, Mechanisms of Malnutrition in Cirrhosis with Portosystemic Shunting (5R01GM119174-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9952384. Licensed CC0.

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