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-1? 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-1? 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.
Skeletal muscle atrophy is a significant component of many chronic diseases either induced by intrinsic properties of the disease and/or chronic disuse. We have identified a common component of muscle atrophies in many disease states that is a degeneration of the mitochondria, the powerhouse of the cell, in the muscle. The proposed studies will unveil novel roles and mechanisms of mitochondrial degeneration in muscle atrophy and provide evidence for new therapies to combat this condition. Nicholas P. Greene, PhD
| Brown, Jacob L; Rosa-Caldwell, Megan E; Lee, David E et al. (2017) Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. J Cachexia Sarcopenia Muscle 8:926-938 |
