# Skeletal muscle sarcomere function in health and disease

> **NIH AR R01** · UNIVERSITY OF MINNESOTA · 2026 · $504,129

## Abstract

Abstract
Skeletal muscle accounts for 40% of body mass and defines in significant ways who we are as human beings.
From the essential underpinnings of breathing, to the basic day-to-day movements of sitting, standing, and
walking, skeletal muscle function enables the fullness of the human condition. Numerous skeletal muscle
diseases cause marked contractile dysfunction leading to significantly diminished overall wellbeing and lifespan
in humans. Therefore, preventing or reversing muscle dysfunction has significant health relevance. This proposal
focuses on the sarcomere - the functional unit of striated muscle – known to underlie multiple forms of contractile
dysfunction. In Nemaline myopathy, severe muscle weakness arises from hypoactive sarcomeres, while the
severe muscle contractures characteristic of Distal Arthrogryposis stem from hyperactive sarcomeres. Other
disorders, including inherited Muscular dystrophies, also involve altered sarcomere function. These diseases
establish the sarcomere as a crucial, yet highly underserved, target for therapeutic intervention. Skeletal muscle
diseases involving defective sarcomeres have no cure or effective treatments. A major challenge to progress
centers on the inherent complexities of sarcomere regulation. Recently, novel ON/OFF myosin cross-bridge
activation states under mechano-sensing regulatory control have been proposed to interface with the troponin-
tropomyosin system to regulate contraction. Working together, through dynamic inter-myofilament signaling, this
new view of sarcomere regulation has significant implications for muscle health and disease. To date, the data
supporting this model derives mainly from biophysical studies, with physiological relevance unclear and critical
to elucidate. We developed and validated a novel FRET-based sarcomere activation biosensor integrated into
the myofilaments of intact skeletal muscle. Preliminary data shows the biosensor detects conformational
changes in troponin, serving

## Key facts

- **NIH application ID:** 11326310
- **Project number:** 5R01AR079477-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** JOSEPH Mark METZGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AR
- **Fiscal year:** 2026
- **Award amount:** $504,129
- **Award type:** 5
- **Project period:** 2022-07-01T00:00:00 → 2027-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11326310

## Citation

> US National Institutes of Health, RePORTER application 11326310, Skeletal muscle sarcomere function in health and disease (5R01AR079477-05). Retrieved via AI Analytics 2026-07-14 from https://api.ai-analytics.org/grant/nih/11326310. Licensed CC0.

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