# Slow myosin binding protein-C in skeletal muscle physiology

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $453,512

## Abstract

PROJECT SUMMARY: The distal arthrogryposes (DA) are a heterogeneous group of disorders characterized
by congenital nonprogressive joint contractures associated with muscle weakness. Depending on the gene
involved and the specific mutation, inheritance is typically autosomal dominant with variable expression and
incomplete penetrance. Current clinical classification identifies eleven different discrete syndromes with several
associated with mutations in sarcomere genes including slow skeletal myosin binding protein-C (MYBPC1).
Recently, a homozygous recessive mutation in MYBPC1 was linked to a severe form of DA, lethal congenital
contracture syndrome type 4 (LCCS4). Despite the increasing association of DA syndromes with specific genetic
mutations, molecular mechanisms that underlie skeletal muscle weakness that presumably lead to disabling
contractures are poorly understood. As these mechanisms are unknown and, specifically, little is known about
how sMyBP-C regulates muscle function in vivo, current therapies are largely ineffective and relegated to
symptomatic physical therapy.
The overall long-term goal of our research program has been to define the contribution of the myosin binding
protein-C (MyBP-C) proteins in health and disease. These sarcomeric-specific proteins are known to regulate
striated muscle contractility via modulating actomyosin function. Three MyBP-C paralogs exist, namely slow
skeletal MyBP-C (sMyBP-C), fast skeletal (fMyBP-C), and cardiac MyBP-C, and encoded by separate genes.
The specific goal of this proposal is to define the physiologic mechanisms underlining how mutations in sMyBP-
C lead to muscle dysfunction and contractures. In our preliminary studies, we determined that mouse pups that
are homozygous global sMyBP-C null (Mybpc1-/-), similar to the human LCCS4 phenotype, all died within the
first day of birth and exhibited tremors secondary to muscle atrophy. We demonstrated that muscle creatine
kinase Cre- and human a-skeletal actin-Cre/Tamoxifen-mediated sMyBP-C ablation (Mybpc1fl/fl) resulted in
significant muscle weakness in postnatal and adult stages, respectively. Finally, we showed in transgenic mice
overexpressing Mybpc1Tg under the control of the human a-skeletal actin promoter that sMyBP-C replaces
fMyBP-C impairing fast muscle type function.
Based on these data, we hypothesize that sMyBP-C acts as a key regulator of striated muscle formation and
function in both slow and fast muscle types. The planned experiments will systematically define whether (i)
sMyBP-C is essential for normal formation of muscle in prenatal and perinatal stages, (ii) sMyBP-C is required
for skeletal muscle function in postnatal and adult stages, and (iii) sMyBP-C and fMyBP-C transcomplement
each other. We anticipate that addressing these key questions will drive mechanistic understanding of how
sMyBP-C regulates skeletal muscle physiology across developmental stages. Consequently, this proposal will
identify therapeutic targets to im...

## Key facts

- **NIH application ID:** 10071545
- **Project number:** 1R01AR078001-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Sakthivel Sadayappan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,512
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071545

## Citation

> US National Institutes of Health, RePORTER application 10071545, Slow myosin binding protein-C in skeletal muscle physiology (1R01AR078001-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071545. Licensed CC0.

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