PROJECT SUMMARY
Muscle atrophy is a hallmark of many chronic diseases resulting in impaired function and reduced quality and
quantity of life. However, current interventions to prevent muscle atrophy are not fully efficacious. Therefore, a
critical need remains to fully elucidate mechanisms of muscle atrophy. We have evidence of muscle wasting in
severe obesity associated with altered mitochondrial biogenesis and content and have acquired evidence of
dysregulated mitochondrial quality control in cancer cachexia (CC) and disuse muscle atrophies. Our preliminary
data in the Apc(Min/+) mouse model of CC suggest derangements in mitochondrial quality control occur
before the onset of cachexia, initiated by impaired mitochondrial biogenesis and fusion. Hence, mitochondrial
derangements may initiate development of muscle atrophies. In fact, our more recent evidence using Lewis Lung
Carcinoma (LLC) implantation suggests mitochondrial degeneration begins as soon as 2 wks following tumor
implantation while body and muscle mass loss do not occur until 4 wks post, thus, suggesting mitochondrial
derangements are common among atrophies and may precede muscle atrophy. However, whether this is
true among atrophies and the commonalities in these mitochondrial degenerations is unknown.
Atrophies are associated with alterations in circulating factors including cytokines and other peptides. Recent
preliminary evidence in our laboratory now implicates secreted factors inducing mitochondrial degeneration, as
treatment of C2C12 myocytes with media from LLC cells induced mitochondrial degeneration. However, the
extent of this impact and what factors mediate this impact are unknown. Additionally, we reported that PGC-1a
is sufficient to promote mitochondrial quality control processes, while mitochondrial reactive oxygen species
(ROS) can be associated with induction of atrogenes. Therefore, we will determine if promoting mitochondrial
quality can alleviate muscle atrophies using PGC-1a and mitochondrial catalase (MCAT, mitochondrial ROS
scavenger) transgenic mice to attempt to prevent muscle atrophy. Our central hypothesis is: mitochondrial
derangements, induced by bloodborne factors, are an initiating event in the development of muscular
atrophies in multiple conditions.
Specific Aim 1. Define mitochondrial derangements associated with disuse and CC induced atrophies.
Specific Aim 2. Determine if promotion of mitochondrial quality is sufficient to alleviate muscle atrophy
in disuse and CC and ascertain novel bloodborne factors impairing mitochondrial quality in atrophy.