Mechanism of mitochondria-induced proteostatic signaling and progressive muscle atrophy during aging.

Muscle atrophy (or wasting) is defined by reduced myofiber size and number, which increases morbidity and
mortality and decreases quality of life. One of the mechanisms of muscle atrophy is the loss of proteostatic
balance. When protein degradation exceeds synthesis, protein content is decreased to reduce myofiber size
and muscle mass. How the balance between protein synthesis and degradation is disturbed in diseased and
aged skeletal muscle in unknown. Mitochondrial dysfunction plays an important role in skeletal muscle atrophy
under many disease conditions and during normative aging, with the underlying mechanism remaining poorly
understood. Perturbations in oxidative phosphorylation and the subsequent increase in reactive oxygen
species production, collectively termed “bioenergetic defects”, have been proposed to drive muscle loss.
However, accumulating evidence suggests that substantial levels of bioenergetic deficiency and oxidative
stress are insufficient to cause muscle wasting. Therefore, if mitochondrial dysfunction does indeed result in
muscle loss, it may involve bioenergetically independent factors. The Chen lab recently found that various
forms of mitochondrial damage can reduce mitochondrial protein import. This causes proteostatic stress in the
cytosol, termed mitochondrial Precursor Overaccumulation Stress (mPOS), followed by global remodeling of
proteostasis. We recently generated a transgenic mouse line that moderately overexpresses the mitochondrial
inner membrane protein, Ant1. We found that Ant1-induced mitochondrial protein import stress causes
progressive muscle atrophy, accompanied by reduction of mitochondrial respiration. However, whether muscle
atrophy is caused by bioenergetic deficiency or bioenergetic-independent stressors remains unknown.
Interestingly, RNA-seq analysis revealed a robust activation of the integrated stress response (ISR), which in
turn represses global protein synthesis and activates autophagy. ISR activation is commonly found in tissues
derived from patients with mitochondrial disease. Using this unique mouse model, we propose to determine the
molecular mechanisms of mitochondria-induced muscle atrophy and ISR activation. In Aim 1, we will determine
the mechanism by which mitochondrial protein import stress induces muscle wasting. In Aim 2, we will
determine whether ISR activation protects skeletal muscle from myofiber death and myopathy in the setting of
mPOS. The long-term goal of this project is to understand how bioenergetics-independent mitochondrial stress
signaling promotes chronic muscle wasting in normative and non-normative aging. The results of this
application may help establish a bioenergetics-independent pathway for treating mitochondria-induced muscle
disease and possibly sarcopenia.

Grant Number: 5F30AG082400-03
NIH Institute/Center: NIH
Principal Investigator: Nicholas Brennan