Marc-André Caron

Comparative assessment of the quadriceps and the diaphragm in patients with COPD

Chronic obstructive pulmonary disease (COPD) and other chronic diseases such as heart failure are accompanied by skeletal muscle alterations that further enhance morbidity and mortality in affected individuals. Several studies have highlighted important structural and biochemical modifications in limb and respiratory muscles in COPD. Reviewing the similarities and differences between the two most studied muscles in COPD, the quadriceps and the diaphragm, may be helpful in providing important clues about the mechanisms underlying muscle changes associated with this disease. Although oxidative stress is present in both muscles, other muscle alterations are clearly distinct between the quadriceps and the diaphragm. For example, the oxidative metabolism varies in opposite directions, the diaphragm exhibiting increased resistance to fatigue while the quadriceps in COPD is characterized by premature fatigability. Differences in muscle phenotypic expression between the diaphragm and the quadriceps indicate that, in addition to systemic factors, the local microenvironment must participate in the reorganization seen in these two skeletal muscles in COPD.

Profiling of mRNA Expression in Quadriceps of Patients with COPD and Muscle Wasting

Peripheral muscle wasting is a feature of chronic obstructive pulmonary disease (COPD). Potent therapeutic strategies are needed to improve peripheral muscle mass in these patients. We hypothesized that the evaluation of the mRNA expression profile of quadriceps muscle could be useful in identifying key biochemical pathways involved in the wasting process. We monitored mRNA expression profile of quadriceps muscle in four patients with COPD with muscle atrophy (age: 71.3 ± 2.1 years, mean SD; FEV1 28.3 ± 10.8 % predicted) and four control subjects (age: 66.5 ± 1.3 years) using HuU95v2 gene chips. Fifty-seven mRNAs transcripts (0.5%) were found to be differentially expressed in muscles of COPD patients (i.e., p < 0.01). Among them, forkhead box O -1 and -3 and insulin-like growth factor-1 expressions being significantly elevated in COPD subjects. Concomitantly, a significant reduction in mRNA expression of two myofilament proteins was observed. Energy production appears to be impaired as indicated by the significant rise in nicotinamide N-methyltransferase mRNA expression. This study provides for the first time evidence that genes are selectively expressed in limb muscles of COPD patients and further research need to focus on their functional roles in the pathogenesis of muscle dysfunction.

Hypoxia alters contractile protein homeostasis in L6 myotubes

Since hypoxia might contribute to the development of muscle atrophy, we wished to provide direct evidence linking hypoxia to muscle atrophy. By evaluating protein degradation and synthesis in hypoxic myotubes we found a significant reduction in total protein content. Using functional assays we observed protein degradation elevation in the first 24 h while synthesis was maintained during this period and then significantly decrease at 48 h. These results demonstrate a temporal regulation of protein homeostasis, whereby elevated protein degradation is followed by a reduction in synthesis. These results are comparable to the cellular adaptation seen during development of muscle atrophy.

Alterations in Skeletal Muscle Cell Homeostasis in a Mouse Model of Cigarette Smoke Exposure

Background Skeletal muscle dysfunction is common in chronic obstructive pulmonary disease (COPD), a disease mainly caused by chronic cigarette use. An important proportion of patients with COPD have decreased muscle mass, suggesting that chronic cigarette smoke exposure may interfere with skeletal muscle cellular equilibrium. Therefore, the main objective of this study was to investigate the kinetic of the effects that cigarette smoke exposure has on skeletal muscle cell signaling involved in protein homeostasis and to assess the reversibility of these effects. Methods A mouse model of cigarette smoke exposure was used to assess skeletal muscle changes. BALB/c mice were exposed to cigarette smoke or room air for 8 weeks, 24 weeks or 24 weeks followed by 60 days of cessation. The gastrocnemius and soleus muscles were collected and the activation state of key mediators involved in protein synthesis and degradation was assessed. Results Gastrocnemius and soleus were smaller in mice exposed to cigarette smoke for 8 and 24 weeks compared to room air exposed animals. Pro-degradation proteins were induced at the mRNA level after 8 and 24 weeks. Twenty-four weeks of cigarette smoke exposure induced pro-degradation proteins and reduced Akt phosphorylation and glycogen synthase kinase-3β quantity. A 60-day smoking cessation period reversed the cell signaling alterations induced by cigarette smoke exposure. Conclusions Repeated cigarette smoke exposure induces reversible muscle signaling alterations that are dependent on the duration of the cigarette smoke exposure. These results highlights a beneficial aspect associated with smoking cessation.

L'atteinte du diaphragme et du quadriceps dans la BPCO: une manifestation systémique de cette maladie ?

INTRODUCTION Chronic obstructive pulmonary disease (COPD) is often accompanied by skeletal muscle alterations, resulting in enhanced morbidity and mortality. STATE OF THE ART Many studies have highlighted important structural and biochemical modifications in limb and respiratory muscles in COPD. Reviewing the similarities and differences between the two most studied muscles in COPD, the quadriceps and the diaphragm, may provide important clues about the mechanisms dictating muscle changes that occur in this disease. PERSPECTIVES Though these two muscle groups share a common systemic environment, discrepancies are observed in their respective alterations. These phenotypic differences suggest that, in addition to systemic factors, the local microenvironment must participate in the reorganization seen in these two muscles in COPD. CONCLUSIONS The current review introduces the alterations observed in the quadriceps and diaphragm in the context of COPD and suggests possible signaling pathways involved in the development of muscle dysfunction.

Skeletal Muscle Dysfunction

Chronic obstructive pulmonary disease (COPD) is highly prevalent and the burden of this disease is only expected to increase in the coming 15–20 years. Once viewed as a disease limited to the lung, COPD is now recognized as a multisystemic disease with various organ dysfunctions. Skeletal muscle dysfunction is one of the most devastating systemic manifestations of COPD. Skeletal muscle dysfunction is such a reality in COPD that, depending on the clinical situations, 20–35% of the patients refer to leg fatigue as the main cause of exercise cessation, whereas 41% consider it to be at least a major contributor to exercise limitation.

Respiratory and Non-respiratory Muscle Dysfunction in COPD

Dysfunction of respiratory and limb muscles is recognized as a major systemic manifestation of COPD. This dysfunction further increases the disease’s morbidity and should be properly evaluated. The aim of this chapter is to summarize the current knowledge on the structural and functional adaptations of both muscle groups in response to COPD. An overview of the possible mechanisms that could explain the development of muscle dysfunction in COPD is also provided. Finally, a summary of the available treatments of muscle dysfunction is presented and their efficiency is discussed.

Study of the Relation between Hypoxia and Muscle Atrophy

Background : Skeletal muscle atrophy is an important feature of chronic obstructive pulmonary disease (COPD) and it is recognized to have considerable clinical impacts. Unfortunately, factors contributing to muscle wasting in COPD are poorly understood. Hypoxemia is typical in COPD and several evidences link hypoxic conditions and protein breakdown. We propose that hypoxia participate to muscle atrophy by increasing Ubiquitin-Proteasome (UP) system activity and by decreasing the activity of IGF/PI3K/Akt synthesis pathway. Methods: To test this hypothesis, L6 muscle myotubes were either exposed to hypoxia (1% O2) or normoxia (21% O2). Results: After 24 hours of hypoxic exposure, we found a significant rise in the chymotrypsin and caspase-like 20S proteasome activities. Proteolysis was confirmed by an accumulation of a 14 kDa actin fragment during hypoxia. An elevation of Atrogin-1 mRNA expression was also observed in similar conditions. A decline in Akt phosphorylation was noticed in hypoxia. These changes were attenuated by insulin treatment. Conclusion: Proteolysis is accentuated in myotubes exposed to hypoxia and the UP system appears to be involved. In addition, protein synthesis seems to be affected as a lower Akt activity was observed. However, the IGF/PI3K/Akt pathway can still be stimulated by a suitable signal suggesting that therapies targeting this pathway are conceivable.