# Loss of Numb in Muscle Dysfunction in Aging

> **NIH NIH R01** · BRONX VETERANS MEDICAL RESEARCH FDN · 2021 · $458,565

## Abstract

Sarcopenia and weakness are inevitable consequences of normal aging that reduce function, predispose to
falls and fractures and are thus associated with significant morbidity and healthcare costs. A growing body of
evidence implicates weakness and loss of muscle power as important contributors to falls in the elderly;
proposed mechanisms include reduced neural drive, loss of fast-twitch fibers, infiltration of muscle by adipose
or other tissue types, dysfunction of the myofibrillar apparatus, or impairments in excitation contraction (E-C)
coupling. Ineffective E-C coupling is thought to be an important contributor to age-related muscle weakness.
EC-Coupling links depolarization of the sarcolemma to a rise in cytosolic calcium concentrations which in turn
causes shortening of actin-myosin fibrils and muscle contraction. This application focuses on roles of the
adaptor protein Numb in regulation of cytosolic calcium transients required for E-C coupling. We propose that
reductions in Numb expression impair E-C coupling and contribute to aging-associated weakness. Numb has
critical roles in cell fate determination, asymmetric cell division and vesicular trafficking. In skeletal muscle,
Numb is required for satellite cell proliferation and enhances myogenic differentiation potential. No studies
have investigated roles of Numb in skeletal muscle E-C coupling or investigated whether reduced Numb
expression contributes to weakness during aging. Our preliminary studies show that Numb is present in
skeletal muscle fibers where it localizes near DHPR. Expression of Numb was reduced in muscles from 20-
month old mice. A knockout of Numb and NumbL (a closely related protein with overlapping functions) in
skeletal muscle fibers reduced muscle strength. Studies of primary cultures of mouse myoblasts revealed that
a knockdown of Numb reduced the caffeine-induced rise in intracellular calcium concentration. These
observations provide compelling evidence for a role of Numb in muscle force production, localize Numb to the
triad, and implicate Numb in regulating calcium transients in skeletal muscle fibers. The findings also implicate
reduced Numb expression as a causal determinant of impaired E-C coupling of aging. We hypothesize that: 1)
diminished specific force generation in our Numb/NumbL double-knockouts is due to reduced Numb
expression, 2) Numb is required for proper regulation of EC-coupling because 3) Numb regulates release by
RyR1 of calcium stored in the SR and absence of Numb depletes SR calcium stores and 4) that age-related
decreases in Numb expression are a cause of weakness. To test these hypotheses we will: Aim 2, Determine
the cellular and molecular basis for muscle weakness resulting from Numb/NumbL knockdowns; Aim 2,
Determine the role of reduced Numb expression in aging-related declines in force production.

## Key facts

- **NIH application ID:** 10208684
- **Project number:** 5R01AG060341-04
- **Recipient organization:** BRONX VETERANS MEDICAL RESEARCH FDN
- **Principal Investigator:** Marco Brotto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $458,565
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10208684

## Citation

> US National Institutes of Health, RePORTER application 10208684, Loss of Numb in Muscle Dysfunction in Aging (5R01AG060341-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10208684. Licensed CC0.

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