The maintenance of mitochondrial integrity is critical for muscle health. Mitochondria, indeed, play vital roles in a wide range of cellular processes, including energy supply, Ca²⁺ homeostasis, retrograde signaling, cell death, and many others. All mitochondria-containing cells, including skeletal muscle cells, dispose of several pathways to maintain mitochondrial health, including mitochondrial biogenesis, mitochondrial-derived vesicles, mitochondrial dynamics (fusion and fission process shaping mitochondrial morphology), and mitophagy—the process in charge of the removal of mitochondria though autophagy. The loss of skeletal muscle mass (atrophy) is a major health problem worldwide, especially in older people. Currently, there is no treatment to counteract the progressive decline in skeletal muscle mass and strength that occurs with aging, a process termed sarcopenia. There is increasing data, including our own, suggesting that accumulation of dysfunctional mitochondria contributes to the development of sarcopenia. Impairments in mitochondrial dynamics and mitophagy were recently proposed to contribute to sarcopenia. This review summarizes the current state of knowledge on the role played by mitochondrial dynamics and mitophagy in skeletal muscle health and in the development of sarcopenia. We also highlight recent studies showing that enhancing mitophagy in skeletal muscle is a promising therapeutic target to prevent or even treat skeletal muscle dysfunction in the elderly.

Rationale: Controlled mechanical ventilation (CMV) results in atrophy of the human diaphragm. The autophagy-lysosome pathway (ALP) contributes to skeletal muscle proteolysis, but its contribution to diaphragmatic protein degradation in mechanically ventilated patients is unknown. Objectives: To evaluate the autophagy pathway responses to CMV in the diaphragm and limb muscles of humans and to identify the roles of FOXO transcription factors in these responses. Methods: Muscle biopsies were obtained from nine control subjects and nine brain-dead organ donors. Subjects were mechanically ventilated for 2 to 4 hours and 15 to 276 hours, respectively. Activation of the ubiquitin-proteasome system was detected by measuring mRNA expressions of Atrogin-1, MURF1, and protein expressions of UBC2, UBC4, and the α subunits of the 20S proteasome (MCP231). Activation of the ALP was detected by electron microscopy and by measuring the expressions of several autophagy-related genes. Total carbonyl content and HNE-protein adduct formation were measured to assess oxidative stress. Total AKT, phosphorylated and total FOXO1, and FOXO3A protein levels were also measured. Measurements and Main Results: Prolonged CMV triggered activation of the ALP as measured by the appearance of autophagosomes in the diaphragm and increased expressions of autophagy-related genes, as compared with controls. Induction of autophagy was associated with increased protein oxidation and enhanced expression of the FOXO1 gene, but not the FOXO3A gene. CMV also triggered the inhibition of both AKT expression and FOXO1 phosphorylation. Conclusions: We propose that prolonged CMV causes diaphragm disuse, which, in turn, leads to activation of the ALP through oxidative stress and the induction of the FOXO1 transcription factor.

Skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease Ho Cheol Kim1, Mahroo Mofarrahi2, Sabah NA Hussain21Department of Internal Medicine, College of Medicine, Gyeongsang National University, Gyeongsang University Hospital, Jinju, Korea; 2Critical Care and Respiratory Divisions, Royal Victoria Hospital, McGill University Health Centre, Montreal, Quebec, Canada Chronic obstructive pulmonary disease (COPD) is a debilitating disease characterized by inflammation-induced airflow limitation and parenchymal destruction. In addition to pulmonary manifestations, patients with COPD develop systemic problems, including skeletal muscle and other organ-specific dysfunctions, nutritional abnormalities, weight loss, and adverse psychological responses. Patients with COPD often complain of dyspnea on exertion, reduced exercise capacity, and develop a progressive decline in lung function with increasing age. These symptoms have been attributed to increases in the work of breathing and in impairments in gas exchange that result from airflow limitation and dynamic hyperinflation. However, there is mounting evidence to suggest that skeletal muscle dysfunction, independent of lung function, contributes signifi cantly to reduced exercise capacity and poor quality of life in these patients. Limb and ventilatory skeletal muscle dysfunction in COPD patients has been attributed to a myriad of factors, including the presence of low grade systemic inflammatory processes, nutritional depletion, corticosteroid medications, chronic inactivity, age, hypoxemia, smoking, oxidative and nitrosative stresses, protein degradation and changes in vascular density. This review briefly summarizes the contribution of these factors to overall skeletal muscle dysfunction in patients with COPD, with particular attention paid to the latest advances in the field.Keywords: skeletal muscles, chronic obstructive pulmonary disease, diaphragm, quadriceps, fatigue, disuse, atrophy, smoking, exercise

Mitochondrial injury develops in skeletal muscles during the course of severe sepsis. Autophagy is a protein and organelle recycling pathway which functions to degrade or recycle unnecessary, redundant, or inefficient cellular components. No information is available regarding the degree of sepsis-induced mitochondrial injury and autophagy in the ventilatory and locomotor muscles. This study tests the hypotheses that the locomotor muscles are more prone to sepsis-induced mitochondrial injury, depressed biogenesis and autophagy induction compared with the ventilatory muscles. Adult male C57/Bl6 mice were injected with i.p. phosphate buffered saline (PBS) or E. coli lipopolysaccharide (LPS, 20 mg/kg) and sacrificed 24 h later. The tibialis anterior (TA), soleus (SOLD) and diaphragm (DIA) muscles were quickly excised and examined for mitochondrial morphological injury, Ca⁺⁺ retention capacity and biogenesis. Autophagy was detected with electron microscopy, lipidation of Lc3b proteins and by measuring gene expression of several autophagy-related genes. Electron microscopy revealed ultrastructural injuries in the mitochondria of each muscle, however, injuries were more severe in the TA and SOL muscles than they were in the DIA. Gene expressions of nuclear and mitochondrial DNA transcription factors and co-activators (indicators of biogenesis) were significantly depressed in all treated muscles, although to a greater extent in the TA and SOL muscles. Significant autophagosome formation, Lc3b protein lipidation and upregulation of autophagy-related proteins were detected to a greater extent in the TA and SOL muscles and less so in the DIA. Lipidation of Lc3b and the degree of induction of autophagy-related proteins were significantly blunted in mice expressing a muscle-specific IκBα superrepresor. We conclude that locomotor muscles are more prone to sepsis-induced mitochondrial injury, decreased biogenesis and increased autophagy compared with the ventilatory muscles and that autophagy in skeletal muscles during sepsis is regulated in part through the NFκB transcription factor.

In this study, we identified whether mitogen‐activated protein kinases (MAPKs) mediate the effects of angiopoietin‐1 (Ang‐1) on endothelial cell apoptosis. Exposure of human umbilical vein endothelial cells to Ang‐1 (300 ng/ml) evoked within 15–30 min a 15‐fold and a 5‐fold increase in phosphorylation of ERK1/2 and p38 MAPKs, respectively. Inhibitors of the PI‐3 kinase pathway attenuated Ang‐1‐induced ERK1/2 phosphorylation at a level up‐stream from Raf and MEK1/2, but these inhibitors augmented Ang‐1‐induced p38 phosphorylation. When serum and growth supplements were withdrawn, the percentage of endothelial apoptosis tripled over 24 h compared with control cells. The presence of Ang‐1 (300 ng/ml) significantly attenuated endothelial cell apoptosis and inhibited caspase‐9, ‐7, and ‐3 activation. These antiapoptotic effects were augmented when a p38 inhibitor was combined with Ang‐1, whereas inhibition of ERK1/2 eliminated the antiapoptotic properties of Ang‐1. We conclude that both anti‐ (ERK1/2) and pro‐ (p38) apoptotic members of MAPKs are simultaneously activated by Ang‐1 in endothelial cells and that activation of ERK1/2 by Ang‐1 is mediated through the PI‐3 kinase pathway. The strong antiapoptotic effects of the ERK and the PI‐3 kinase pathways mask the proapoptotic function of p38 MAPKs resulting in net attenuation of apoptosis by Ang‐1.

Relatively low levels of reactive oxygen species (ROS) produced inside resting skeletal muscles play important functions in cell signaling. When ROS production increases to levels beyond the buffering capacity of muscle antioxidant systems, a state of oxidative stress develops, which leads to skeletal muscle contractile dysfunction. A clear association between oxidative stress and depressed skeletal muscle performance has been described in several acute and chronic conditions, such as systemic inflammation and chronic obstructive lung diseases. The observation that the levels of oxidant-derived posttranslational protein modifications, including protein carbonylation, are elevated inside skeletal muscle fibers when oxidative stress develops suggest that these modifications play important roles in regulating muscle function. This proposal is supported by recent studies that unveiled that several myofilament (myosin heavy chain and actin), mitochondrial (aconitase, creatine kinase), and cytosolic (enolase, aldolase and glyceraldehyde 3-phosphate dehydrogenase and carbonic anhydrase III) proteins are carbonylated inside skeletal muscle fibers in many animal models of muscle dysfunction, and in humans with impaired skeletal muscle contractility. However, the functional importance of carbonylation in determining the function of muscle-specific proteins and the precise contribution of carbonylation-induced dysfunction of these proteins to overall muscle contractile deficit in various pathologies remain to be determined. Antioxid. Redox Signal. 12, 417–429.