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Published on: March 12, 2016
Age-related changes of cell death pathways in rat extraocular muscle
Colleen A McMullen1, Amy L Ferry, Jorge L Gamboa
1Department of Physiology, University of Kentucky, 800 Rose St., MS508, Lexington, KY 40536-0298, USA. cmcmu2@email.uky.edu
Abstract:
Changes in the structure and function of aging non-locomotor muscles remains understudied, despite their importance for daily living. Extraocular muscles (EOMs) have a high incidence of age-related mitochondrial defects possibly because of the metabolic stress resulting from their fast and constant activity. Apoptosis and autophagy (type I and II cell death, respectively) are linked to defects in mitochondrial function and contribute to sarcopenia in hind limb muscles. Therefore, we hypothesized that apoptosis and autophagy are altered with age in the EOMs. Muscles from 6-, 18-, and 30-month-old male Fisher 344-Brown Norway rats were used to investigate type I cell death, caspase-3, -8, -9, and -12 activity, and type II cell death. Apoptosis, as measured by TUNEL positive nuclei, and mono- and oligo-nucleosomal content, did not change with age. Similarly, caspase-3, -8, -9, and -12 activity was not affected by aging. By contrast, autophagy, as estimated by gene expression of Atg5 and Atg7, and protein abundance of LC3 was lower in EOMs of aged rats. Based on these data, we suggest that the decrease in autophagy with age leads to the accumulation of damaged organelles, particularly mitochondria, which results in the decrease in function observed in EOM with age.
Insights
Aging extraocular muscles show decreased autophagy, not apoptosis. This decline in cellular recycling may cause mitochondrial damage and functional loss in older rats.
Area of Science:
- Gerontology
- Muscle Physiology
- Cellular Biology
Background:
- Aging non-locomotor muscles, like extraocular muscles (EOMs), are understudied despite their importance.
- EOMs exhibit age-related mitochondrial defects due to high metabolic demands.
- Apoptosis and autophagy are cellular processes linked to mitochondrial dysfunction and muscle aging.
Purpose of the Study:
- To investigate age-related changes in apoptosis (type I cell death) and autophagy (type II cell death) in rat EOMs.
- To determine if these cell death pathways contribute to functional decline in aging EOMs.
Main Methods:
- Analysis of EOMs from young (6-month), mature (18-month), and aged (30-month) male Fisher 344-Brown Norway rats.
- Assessment of apoptosis markers (TUNEL, nucleosomal content) and caspase activity (caspase-3, -8, -9, -12).
- Evaluation of autophagy markers (Atg5, Atg7 gene expression, LC3 protein abundance).
Main Results:
- Apoptosis and caspase activity remained unchanged with age in EOMs.
- Autophagy markers (Atg5, Atg7, LC3) were significantly lower in aged rat EOMs compared to younger groups.
- No age-related increase in apoptotic cell death was observed.
Conclusions:
- Aging in EOMs is characterized by reduced autophagy, not increased apoptosis.
- Decreased autophagy may lead to the accumulation of damaged organelles, particularly mitochondria.
- This accumulation likely contributes to the functional decline observed in aging EOMs.
