Mitochondrial signaling contributes to disuse muscle atrophy.

It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.

Short-duration mechanical ventilation enhances diaphragmatic fatigue resistance but impairs force production.

STUDY OBJECTIVE: s: Mechanical ventilation (MV) is a life-support measure for patients who cannot maintain adequate alveolar ventilation. Following prolonged MV, difficulty in weaning patients from the ventilator can occur, and it has been postulated that difficult weaning is linked to respiratory muscle dysfunction. We tested the hypothesis that 18 h of controlled MV will diminish diaphragmatic maximal tetanic specific tension (force per cross-sectional area of muscle) without impairing diaphragmatic fatigue resistance. DESIGN: To test this postulate, adult Sprague-Dawley rats were randomly classified into one of two experimental groups: (1) control group (n = 8), and (2) 18-h MV group (n = 6). MV-treated animals were anesthetized, tracheostomized, and received room air ventilation. Animals in the control group were acutely anesthetized but did not receive MV. Muscle strips from the mid-costal diaphragm were removed from both experimental groups, and contractile properties were studied in vitro to determine the effects of MV on diaphragmatic endurance and maximal force production. Diaphragmatic endurance was investigated by measuring tension development during repeated contractions throughout a 30-min fatigue protocol. RESULTS: MV resulted in a reduction (p < 0.05) in diaphragmatic maximal specific tension (control group, 26.8 +/- 0.2 Newtons/cm(2) vs MV group, 21.3 +/- 0.6 Newtons/cm(2)). Compared to the control group, diaphragms from MV-treated animals maintained higher (p < 0.05) percentages of the initial force production throughout the fatigue protocol. The observed improvement in fatigue resistance was associated with an increase in diaphragmatic oxidative and antioxidant capacity as evidenced by increases (p < 0.05) in both citrate synthase and superoxide dismutase activities. However, by comparison to the control group, diaphragms from MV-treated animals generated less (p < 0.05) absolute specific force throughout the fatigue protocol. CONCLUSIONS: These data indicate that 18 h of MV enhances diaphragmatic fatigue resistance but impairs diaphragmatic specific tension.

Diaphragm unloading via controlled mechanical ventilation alters the gene expression profile.

RATIONALE: Prolonged controlled mechanical ventilation results in diaphragmatic inactivity and promotes oxidative injury, atrophy, and contractile dysfunction in this important inspiratory muscle. However, the impact of controlled mechanical ventilation on global mRNA alterations in the diaphragm remains unknown. OBJECTIVES: In these experiments, we used an Affymetrix oligonucleotide array to identify the temporal changes in diaphragmatic gene expression during controlled mechanical ventilation in the rat. METHODS: Adult Sprague-Dawley rats were assigned to either control or mechanical ventilation groups (n = 5/group). Mechanically ventilated animals were anesthetized, tracheostomized, and ventilated with room air for 6 or 18 h. Animals in the control group were acutely anesthetized but not exposed to mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Compared with control diaphragms, microarray analysis identified 354 differentially expressed, unique gene products after 6 and 18 h of mechanical ventilation. In general, genes in the cell growth/cell maintenance, stress response, and nucleic acid metabolism categories showed predominant upregulation, whereas genes in the structural protein and energy metabolism categories were predominantly downregulated. CONCLUSIONS: We conclude that mechanical ventilation results in rapid changes in diaphragmatic gene expression, and subsequently, many of these changes may contribute to atrophy and muscle fiber remodeling associated with unloading this primary inspiratory muscle. Importantly, this study also provides new insights into why the diaphragm, after the onset of contractile inactivity, atrophies more rapidly than locomotor skeletal muscles and also highlights unique differences that exist between these muscles in the mRNA response to inactivity.

Mechanical ventilation depresses protein synthesis in the rat diaphragm.

Prolonged mechanical ventilation results in diaphragmatic atrophy and contractile dysfunction in animals. We hypothesized that mechanical ventilation-induced diaphragmatic atrophy is associated with decreased synthesis of both mixed muscle protein and myosin heavy chain protein in the diaphragm. To test this postulate, adult rats were mechanically ventilated for 6, 12, or 18 hours and diaphragmatic protein synthesis was measured in vivo. Six hours of mechanical ventilation resulted in a 30% decrease (p < 0.05) in the rate of mixed muscle protein synthesis and a 65% decrease (p < 0.05) in the rate of myosin heavy chain protein synthesis; this depression in diaphragmatic protein synthesis persisted throughout 18 hours of mechanical ventilation. Real-time polymerase chain reaction analyses revealed that mechanical ventilation, in comparison with time-matched controls, did not alter diaphragmatic levels of Type I and IIx myosin heavy chain messenger ribonucleic acid levels in the diaphragm. These data support the hypothesis that mechanical ventilation results in a decrease in both mixed muscle protein and myosin heavy chain protein synthesis in the diaphragm. Further, the decline in myosin heavy chain protein synthesis does not appear to be associated with a decrease in myosin heavy chain messenger ribonucleic acid.