The role of alterations in mitochondrial dynamics and PGC‐1α over‐expression in fast muscle atrophy following hindlimb unloading

• Published in: The Journal of physiology 2015-04, Vol.593 (8), p.1981-1995
• Main Authors: Cannavino, Jessica, Brocca, Lorenza, Sandri, Marco, Grassi, Bruno, Bottinelli, Roberto, Pellegrino, Maria Antonietta
• Format: Article
• Language: English
• Subjects: Acetyl-CoA Carboxylase - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Hindlimb Suspension - physiology; Male; Mice; Mice, Transgenic; Mitochondria - metabolism; Mitochondrial Dynamics - physiology; Muscle; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Transcription Factors - genetics; Transcription Factors - metabolism; Up-Regulation
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2014.286740

Key points Skeletal muscle atrophy occurs as a result of disuse. Although several studies have established that a decrease in protein synthesis and increase in protein degradation lead to muscle atrophy, little is known about the triggers underlying such processes. A growing body of evidence challenges oxidative stress as a trigger of disuse atrophy; furthermore, it is also becoming evident that mitochondrial dysfunction may play a causative role in determining muscle atrophy. Mitochondrial fusion and fission have emerged as important processes that govern mitochondrial function and PGC‐1α may regulate fusion/fission events. Although most studies on mice have focused on the anti‐gravitary slow soleus muscle as it is preferentially affected by disuse atrophy, several fast muscles (including gastrocnemius) go through a significant loss of mass following unloading. Here we found that in fast muscles an early down‐regulation of pro‐fusion proteins, through concomitant AMP‐activated protein kinase (AMPK) activation, can activate catabolic systems, and ultimately cause muscle mass loss in disuse. Elevated muscle PGC‐1α completely preserves muscle mass by preventing the fall in pro‐fusion protein expression, AMPK and catabolic system activation, suggesting that compounds inducing PGC‐1α expression could be useful to treat and prevent muscle atrophy. The mechanisms triggering disuse muscle atrophy remain of debate. It is becoming evident that mitochondrial dysfunction may regulate pathways controlling muscle mass. We have recently shown that mitochondrial dysfunction plays a major role in disuse atrophy of soleus, a slow, oxidative muscle. Here we tested the hypothesis that hindlimb unloading‐induced atrophy could be due to mitochondrial dysfunction in fast muscles too, notwithstanding their much lower mitochondrial content. Gastrocnemius displayed atrophy following both 3 and 7 days of unloading. SOD1 and catalase up‐regulation, no H2O2 accumulation and no increase of protein carbonylation suggest the antioxidant defence system efficiently reacted to redox imbalance in the early phases of disuse. A defective mitochondrial fusion (Mfn1, Mfn2 and OPA1 down‐regulation) occurred together with an impairment of OXPHOS capacity. Furthermore, at 3 days of unloading higher acetyl‐CoA carboxylase (ACC) phosphorylation was found, suggesting AMP‐activated protein kinase (AMPK) pathway activation. To test the role of mitochondrial alterations we used Tg‐mice overexpressing PG