# Sustained Smad signaling in ALS muscle promotes disease progression through a dysregulated miRNA transcriptome

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons. There is no effective
treatment for ALS and the determinants of disease onset and progression remain poorly understood. ALS
affects veterans disproportionately over the civilian population, and thus is a major research priority for the VA.
There are two major gaps of knowledge in ALS that this application will address: (1) The pathogenic role of the
peripheral neuromusuclar system in the initiation of disease and progression, and (2) The lack of plasma
biomarkers that can aid the clinician in diagnosis, progression rate, and prognosis.
 Skeletal muscle and the neuromuscular junction (NMJ) are the “end organs” of motor neurons and have
been a growing focus as important contributors to ALS pathogenesis and disease progression, but there
remains a large knowledge gap. The earliest pathological findings in ALS are in skeletal muscle including
mitochondrial dysfunction, retraction of motor neuron termini and degeneration of the neuromuscular junction.
In normal states, there is ongoing cross-talk between muscle fibers and motor neurons that maintain the health
of each, including the release of growth factors by muscle such as NT-4, BMP4 and IGF1. In ALS, this
homeostasis is disrupted by the degenerative process coupled with the infiltration of immune cells into the
neuromuscular system. Using skeletal muscle of ALS patients, we have characterized a molecular network of
biomarkers that is induced and activated in the earliest preclinical stages of disease and progressively
increases with disease progression. This network centers around elements of the TGFβ/BMP/Smad signaling
axis and prominently includes Smad8, TGF-β1, 2, 3 and BMP4. In parallel with this axis is a dysregulated
microRNA (miRNA) transcriptome which we characterized by miRNA sequencing of human ALS skeletal
muscle from patient biopsies. In our preliminary studies, we have discovered that Smad8 signaling regulates
many of the components of this aberrant miRNA/mRNA network and that the predicted effect, based on in
silico analysis, would be impairiment of muscle homeostasis, muscle regeneration, NMJ reinnervation and
promotion of neuromuscular inflammation. In other work, we have shown that ALS patients have extensive
infiltration of myeloid cells, including mast cells, neutrophils, and macrophages, in muscle and peripheral nerve
that accelerate disease progression. This background and preliminary data form the basis of our overarching
hypothesis that BMP/TGFβ/Smad signaling in ALS muscle promotes disease progression through a
dysregulated miRNA transcriptome which is sustained by a paracrine loop with infiltrating immune cells.
Furthermore, we hypothesize that components of this molecular network reflect disease progression and thus
may serve as plasma biomarkers that can be used in the clinic to monitor disease progression. We propose 3
aims: (1) Characterize the link between activated Smad8 and dysregu...

## Key facts

- **NIH application ID:** 10699539
- **Project number:** 1I01BX006231-01
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** PETER H KING
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10699539

## Citation

> US National Institutes of Health, RePORTER application 10699539, Sustained Smad signaling in ALS muscle promotes disease progression through a dysregulated miRNA transcriptome (1I01BX006231-01). Retrieved via AI Analytics 2026-07-27 from https://api.ai-analytics.org/grant/nih/10699539. Licensed CC0.

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