CD34 regulates the skeletal muscle response to hypoxia.

Chronic obstructive pulmonary disease (COPD) can sometimes be associated with skeletal muscle atrophy. Hypoxemic episodes, which occur during disease exacerbation and daily physical activity, are frequent in COPD patients. However, the link between hypoxemia and muscle atrophy remains unclear, along with mechanisms of muscle hypoxic stress response. Myogenic progenitors (MPs) and fibro/adipogenic progenitors (FAPs) express CD34 and participate to muscle mass maintenance. Although there is evidence linking CD34 expression and muscle repair, the link between CD34 expression, muscle wasting and the hypoxic stress observed in COPD has never been studied. Using a 2-day model of exposure to hypoxic conditions, we investigated the impact of hypoxia on skeletal muscle wasting and function, and elucidated the importance of CD34 expression in that response. A 2-day exposure to hypoxic conditions induces muscle atrophy, which was significantly worse in Cd34-/- mice compared to wild type (WT). Moreover, the lack of CD34 expression negatively impacts the maximal strength of the extensor digitorum longus muscle in response to hypoxia. Following exposure to hypoxic conditions, FAPs (which support MPs differentiation and myogenesis) are significantly lower in Cd34-/- mice compared to WT animals while the expression of myogenic regulatory factors and degradation factors (Atrogin) are similar. CD34 expression is important in the maintenance of muscle mass and function in response to hypoxic stress. These results highlight a new potential role for CD34 in muscle mass maintenance in hypoxic stress such as observed in COPD.

An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease.

BACKGROUND: Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS: An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS: We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS: Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

Regenerative defect in vastus lateralis muscle of patients with chronic obstructive pulmonary disease.

BACKGROUND: Impaired skeletal muscle regeneration could contribute to the progression of muscle atrophy in patients with chronic obstructive pulmonary disease (COPD). METHODS: Satellite cells and myogenesis-related proteins were compared between healthy subjects and patients with COPD, with or without muscle atrophy. Satellite cells were isolated and cultured to assess their proliferative and differentiation aptitudes. RESULTS: Although satellite cell numbers in muscle samples were similar between groups, the proportion of muscle fibers with central nuclei was increased in COPD. In muscle homogenates, increased expression of MyoD and decreased expression of myogenin and MRF4 were observed in COPD. In cultured satellite cells of patients with COPD, increased protein content was observed for Pax7, Myf5 (proliferation phase) and myogenin (differentiation phase) while myosin heavy chain protein content was significantly lower during differentiation. CONCLUSION: In COPD, the number of central nuclei was increased in muscle fibers suggesting a greater number of attempts to regenerate muscle tissue than in healthy subjects. Myogenesis signaling was also altered in muscle homogenates in patients with COPD and there was a profound reduction in the differentiation potential in this population as indicated by a reduced ability to incorporate myosin heavy chain into newly formed myotubes. Collectively, these results indicate that skeletal muscle regenerative capacity termination is impaired in COPD and could contribute to the progression of muscle atrophy progression in this population.

Preserved function and reduced angiogenesis potential of the quadriceps in patients with mild COPD.

BACKGROUND: Little is known about limb muscle abnormalities in mild COPD. Inactivity and systemic inflammation could play a role in the development of limb muscle dysfunction in COPD. The objective of the present study was to characterize quadriceps function, enzymatic activities and morphometry, levels of plasma inflammatory markers and physical activity levels in daily life (PAdl) in patients with mild COPD (GOLD 1). METHODS: Mid-thigh muscle cross-sectional area (MTCSA), quadriceps strength, endurance, fiber-type distribution, capillarity, pro-angiogenesis factors (VEGF-A, angiopoietin I and II) and muscle oxidative capacity were assessed in 37 patients with mild COPD and 19 controls. Systemic inflammatory markers (CRP, IL-6, TNF-α, Fibrinogen, SP-D) and PAdl were assessed. RESULTS: MTCSA, quadriceps strength and endurance were not different between COPD and controls. Capillarity and muscle oxidative capacity were all preserved in mild COPD. Reduced pro-angiogenesis factor mRNA expression was seen in COPD. The level of moderately active intensity (>3 METs) was significantly lower in mild COPD and, in multiple regression analyses, the level of physical activity was a determinant of muscle oxidative capacity and capillarization. No between-group differences were found regarding muscle oxidative stress while circulating IL-6 levels were elevated in mild COPD. CONCLUSIONS: The quadriceps muscle function was preserved in mild COPD although a reduced potential for angiogenesis was found. The reduced level of daily activities and evidence of systemic inflammation in these individuals suggest that these factors precede the development of overt limb muscle dysfunction in COPD.

Autophagy in locomotor muscles of patients with chronic obstructive pulmonary disease.

RATIONALE: Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if autophagy also contributes to protein degradation. OBJECTIVES: To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction. METHODS: Muscle biopsies were obtained from two cohorts of control subjects and patients with COPD and the numbers of autophagosomes in the vastus lateralis and tibialis anterior muscles, the levels of LC3B protein lipidation, and the expression of autophagy-related genes were measured in the vastus lateralis muscle. To investigate potential pathways that might induce the activation of autophagy, measures were taken of protein kinase B (AKT), mTORC1, and AMPK pathway activation, transcription factor regulation, proteasome activation, and oxidative stress. MEASUREMENTS AND MAIN RESULTS: Autophagy is enhanced in the locomotor muscles of patients with COPD as shown by significantly higher numbers of autophagosomes in affected muscles as compared with control subjects. Autophagosome number inversely correlates with FEV1. In the vastus lateralis, LC3B protein lipidation is increased by COPD and the expression of autophagy-related gene expressions is up-regulated. LC3B lipidation inversely correlates with thigh cross-sectional area, FEV1, and FEV1/FVC ratio. Enhanced autophagy is associated with activation of the AMPK pathway and FOXO transcription factors, inhibition of the mTORC1 and AKT pathways, and the development of oxidative stress. CONCLUSIONS: Autophagy is significantly enhanced in locomotor muscles of stable patients with COPD. The degree of autophagy correlates with severity of muscle atrophy and lung function impairment.

Exploring if and how evidence-based practice of occupational and physical therapists evolves over time: A longitudinal mixed methods national study.

BACKGROUND: Occupational therapists (OTs) and physiotherapists (PTs) are expected to provide evidence-based services to individuals living with disabilities. Despite the emphasis on evidence-based practice (EBP) by professional entry-level programs and professional bodies, little is known about their EBP competencies upon entry to practice and over time or what factors impact EBP use. The aim of the study was to measure and understand how EBP evolves over the first three years after graduation among Canadian OTs and PTs, and how individual and organizational factors impact the continuous use of EBP. METHODS: A longitudinal, mixed methods sequential explanatory study. We administered a survey questionnaire measuring six EBP constructs (knowledge, attitudes, confidence, resources, use of EBP and evidence-based activities) annually, followed by focus group discussions with a subset of survey participants. We performed group-based trajectory modeling to identify trajectories of EBP over time, and a content analysis of qualitative data guided by the Theoretical Domains Framework. RESULTS: Of 1700 graduates in 2016-2017, 257 (response rate = 15%) responded at baseline (T0) (i.e., at graduation), and 83 (retention rate = 32%), 75 (retention rate = 29%), and 74 (retention rate = 29%) participated at time point 1 (T1: one year into practice), time point 2 (T2: two years into practice, and time point 3 (T3: three years into practice) respectively. Group-based trajectory modeling showed four unique group trajectories for the use of EBP. Over 64% of participants (two trajectories) showed a decline in the use of EBP over time. Fifteen practitioners (7 OTs and 8 PTs) participated in the focus group discussions. Personal and peer experiences, client needs and expectations, and availability of resources were perceived to influence EBP the most. CONCLUSIONS: Though a decline in EBP may be concerning, it is unclear if this decline is clinically meaningful and whether professional expertise can offset such declines. Stakeholder-concerted efforts towards the common goal of promoting EBP in education, practice and policy are needed.

Developing multisectoral strategies to promote evidence-based practice in rehabilitation: findings from an end-of-grant knowledge translation symposium.

PURPOSE: Following a longitudinal study to understand how evidence-based practice evolves during the initial years of occupational therapy (OT) and physiotherapy (PT) practice, we held an end-of-grant symposium with representatives from education, practice, research, and policy. The objectives were to: (1) elicit feedback on the implications of the study results; and (2) co-develop a list of actionable recommendations for each sector. METHODS: Qualitative participatory approach. The symposium was held over two half days and consisted of a presentation of study findings, a discussion on the implications of the research for each sector and future recommendations. Discussions were audio recorded, transcribed verbatim and analyzed using qualitative thematic analysis. RESULTS: The themes related to implications of the longitudinal study included: (1) A need to rethink what evidence-based practice (EBP) really is; (2) How to practice EBP; and (3) The continuing challenge of measuring EBP. The co-development of actionable recommendations resulted in nine strategies. CONCLUSIONS: This study highlighted how we may collectively promote EBP competencies in future OTs and PTs. We generated sector-specific avenues that may be pursued to promote EBP and argued for the importance of pooling efforts from the four sectors so that we may achieve the intended ethos of EBP.IMPLICATIONS FOR REHABILITATIONThere is a need to revisit the definition of evidence-based practice (EBP) and the traditional 3-circle model in rehabilitation to include a broader conceptualization of what constitutes evidence.We recommend using EBP measures as tools for self-reflection and professional development that can support practitioners to be reflective and accountable evidence-based practitioners.Optimal promotion of EBP competencies in occupational therapists and physiotherapists should rest upon collaborative efforts from the education, practice, research, and policy sectors.

Expression and functional significance of nicotinamide N-methyl transferase in skeletal muscles of patients with chronic obstructive pulmonary disease.

RATIONALE: Nicotinamide N-methyl transferase (NNMT) is highly expressed in quadriceps muscles of patients with chronic obstructive pulmonary disease (COPD). However, its expression in the diaphragm of these patients has not been assessed. The functional significance of NNMT induction in skeletal muscles of patients with COPD is also unknown. OBJECTIVES: (1) To compare NNMT expressions in the diaphragm and quadriceps muscles of patients with COPD. (2) To identify the influence of proinflammatory cytokines on NNMT expression. (3) To assess the influence of NNMT on indices of myogenesis (satellite cell migration and proliferation) and the defense against oxidative stress. METHODS: Costal diaphragm muscle biopsies were acquired from 13 patients with moderate and severe COPD and 8 control subjects. Quadriceps muscle biopsies were obtained from 12 patients with COPD and 14 control subjects. MEASUREMENTS AND MAIN RESULTS: NNMT expressions were significantly elevated in the diaphragm and quadriceps muscles of patients with COPD; however, the relative induction of NNMT expression was greater in the quadriceps muscle (10-fold) than it was in the diaphragm (2-fold). NNMT expressions correlated negatively with the severity of COPD and limb muscle wasting. In skeletal myoblasts, NNMT expression was significantly induced by IL-6, transforming growth factor beta, and tumor necrosis factor-alpha. Overexpression of NNMT in myoblasts triggered a significant increase in proliferation and migration, but had no influence on cell death. Carbonyl formation, induced by exposing myoblasts to H(2)O(2), was significantly attenuated when NNMT was overexpressed. CONCLUSIONS: Up-regulation of NNMT expression in the skeletal muscles of patients with COPD may represent an adaptive response designed to improve myogenesis and defend against oxidative stress.

Atrophy and hypertrophy signalling of the quadriceps and diaphragm in COPD.

BACKGROUND: Factors involved in the regulation of muscle mass in chronic obstructive pulmonary disease (COPD) are still poorly understood. Comparing the signalisation involved in muscle mass regulation between two muscles with different levels of activation within the same subjects is an interesting strategy to tease out the impact of local (muscle activity) versus systemic factors in the regulation of muscle mass. A study was undertaken to measure and compare the protein levels of p-AKT, AKT, Atrogin-1, p-p70S6K, p-4E-BP1, p-GSK3ß as well as the mRNA expression of Atrogin-1, MuRF1 and FoxO-1 in the quadriceps and the diaphragm of 12 patients with COPD and 7 controls with normal lung function. METHODS: Diaphragm biopsies were obtained during thoracic surgery and quadriceps samples were obtained from needle biopsies. Protein content and mRNA expression were measured by western blot and quantitative PCR, respectively. RESULTS: Increased mRNA expressions of Atrogin-1, MuRF1 and FoxO-1 were found in the quadriceps compared with the diaphragm only in patients with COPD. The quadriceps/diaphragm ratio for MuRF1 was higher in COPD. The protein level of p-p70S6K was decreased in the quadriceps compared with the diaphragm in patients with COPD. The quadriceps/diaphragm ratios of p-p70S6K and p-GSK3ß were lower in patients with COPD than in controls. CONCLUSIONS: These results indicate a greater susceptibility to a catabolic/anabolic imbalance favouring muscle atrophy in the quadriceps compared with the diaphragm in patients with COPD. The balance between the atrophy and hypertrophy signalling is inhomogeneous between respiratory and lower limb muscles, suggesting that local factors are likely to be involved in the regulation of muscle mass in COPD.

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.

Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions.

With trauma, sepsis, cancer, or uremia, animals or patients experience accelerated degradation of muscle protein in the ATP-ubiquitin-proteasome (Ub-P'some) system. The initial step in myofibrillar proteolysis is unknown because this proteolytic system does not break down actomyosin complexes or myofibrils, even though it degrades monomeric actin or myosin. Since cytokines or insulin resistance are common in catabolic states and will activate caspases, we examined whether caspase-3 would break down actomyosin. We found that recombinant caspase-3 cleaves actomyosin, producing a characteristic, approximately 14-kDa actin fragment and other proteins that are degraded by the Ub-P'some. In fact, limited actomyosin cleavage by caspase-3 yields a 125% increase in protein degradation by the Ub-P'some system. Serum deprivation of L6 muscle cells stimulates actin cleavage and proteolysis; insulin blocks these responses by a mechanism requiring PI3K. Cleaved actin fragments are present in muscles of rats with muscle atrophy from diabetes or chronic uremia. Accumulation of actin fragments and the rate of proteolysis in muscle stimulated by diabetes are suppressed by a caspase-3 inhibitor. Thus, in catabolic conditions, an initial step resulting in loss of muscle protein is activation of caspase-3, yielding proteins that are degraded by the Ub-P'some system. Therapeutic strategies could be designed to prevent these events.

Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1α axis.

Increased expression levels of the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1) have been associated with enhanced proliferation and metastasis of several cancer cell types. Hypoxia, a hallmark characteristic of solid tumors, has been linked to an increase in the activity of the ATP-generating AMPK protein. Since Malat1 was recently shown to be upregulated during hypoxia, the objective of this study was to determine the contribution of AMPK in the mechanistic pathways regulating Malat1 expression in low oxygen conditions. Compared to those cultured in 21% O2 conditions, HeLa cells incubated in 1.5% O2 expressed more Malat1 transcripts. This observation was mimicked in HEK293T cells using a synthetic reporter construct containing 5.6 kb of the human Malat1 promoter, suggesting that hypoxia directly impacted Malat1 gene transcription. Interestingly, pharmacological stimulation of AMPK increased Malat1 promoter transactivation in 21% O2 conditions, whereas inhibition of either AMPK or its upstream activator CaMKK completely abolished the augmentation of Malat1 under hypoxia. Pharmacological modulation of LKB1, another major regulator of AMPK, had no impact on Malat1 promoter transactivation, suggesting that calcium inputs are important in the control of Malat1 expression by AMPK. Overexpression of hypoxia-inducible factor-1α (HIF-1α) increased Malat1 expression in 21% O2 conditions, whereas pharmacological inhibition of HIF-1α blocked the impact of hypoxia on the Malat1 promoter. Taken together, these findings strongly suggest that Malat1 expression is regulated in hypoxic conditions by a CaMKK/AMPK/HIF-1α axis. More research is needed in physiological settings to test the clinical relevance of this pathway.

Pulmonary rehabilitation in Canada: A report from the Canadian Thoracic Society COPD Clinical Assembly.

BACKGROUND: Pulmonary rehabilitation (PR) is a recommended intervention in the management of individuals with chronic lung disease. It is important to study the characteristics and capacity of programs in Canada to confirm best practices and identify future areas of program improvement and research. OBJECTIVE: To identify all Canadian PR programs, regardless of setting, and to comprehensively describe all aspects of PR program delivery. The present article reports the results of the survey related to type of program, capacity and program characteristics. METHODS: All hospitals in Canada were contacted to identify PR programs. A representative from each program completed a 175-item online survey encompassing 16 domains, 10 of which are reported in the present article. RESULTS: A total of 155 facilities in Canada offered PR, of which 129 returned surveys (83% response rate). PR programs were located in all provinces, but none in the three territories. Most (60%) programs were located in hospital settings, 24% were in public health units and 8% in recreation centres. The national capacity of programs was estimated to be 10,280 patients per year, resulting in 0.4% of all Canadians with chronic obstructive pulmonary disease (COPD) and 0.8% of Canadians with moderate to severe COPD having access to PR. COPD, interstitial lung disease, and asthma were the most common diagnoses of patients. The majority of programs had at least four health care professionals involved; 9% had only one health care professional involved. CONCLUSION: The present comprehensive survey of PR in Canada reports an increase in the number of programs and the total number of patients enrolled since the previous survey in 2005. However, PR capacity has not kept pace with demand, with only 0.4% of Canadians with COPD having access.

Catabolic/anabolic balance and muscle wasting in patients with COPD.

BACKGROUND: The mechanisms leading to muscle wasting in patients with COPD are still uncertain. This study was undertaken to evaluate the relationships among circulating levels of catabolic factors (ie, interleukin [IL]-6 and cortisol), anabolic factors (ie, bioavailable testosterone [Tbio], dehydroepiandrosterone sulfate [DHEAS], and insulin-like growth factor [IGF]-I), and mid-thigh muscle cross-sectional area (MTCSA) in patients with COPD. METHODS: Serum levels of the above factors were measured in 45 men with COPD (mean [+/- SEM] FEV(1), 43 +/- 3% predicted; mean age, 67 +/- 1 years) and 16 sedentary healthy men of similar age. MTCSA was quantified using CT scanning. Patients with COPD were subdivided into two groups according to the MTCSA (< 70 or >or= 70 cm(2)). RESULTS: There was a greater prevalence of hypogonadism (ie, Tbio, < 2 nmol/L) in patients with COPD compared to control subjects (22% vs 0%, respectively). Patients with an MTCSA of < 70 cm(2) had significantly reduced levels of DHEAS compared to those in healthy subjects (p < 0.01). IL-6 levels were significantly higher in both subgroups of COPD patients compared to those in control subjects (p < 0.005). The cortisol/DHEAS, IL-6/DHEAS, IL-6/Tbio, and IL-6/IGF-I ratios were significantly greater in COPD patients with an MTCSA of < 70 cm(2) compared to those in control subjects (p < 0.05). The cortisol/DHEAS and IL-6/DHEAS ratios were also significantly greater in COPD patients with an MTCSA of < 70 cm(2) than in COPD patients with an MTCSA of >or= 70 cm(2) (p < 0.05). In a stepwise multiple regression analysis, the IL-6/DHEAS ratio explained 20% of the variance in MTCSA (p < 0.005). CONCLUSION: Catabolic/anabolic disturbances were found in COPD patients leading to a shift toward catabolism and possibly to the development of peripheral muscle wasting.

Should all patients with COPD be exercise trained?

Exercise training is one of the most powerful interventions to provide symptomatic relief in patients with chronic obstructive pulmonary disease (COPD). The purpose of this minireview is to discuss how exercise training can improve limb muscle dysfunction in this disease. Various exercise training strategies will be outlined, along with their beneficial effects and potential limitations. Strategies to optimize the gains achievable with exercise training will be presented. Whether exercise training may exert deleterious effects in some patients will also be discussed.

Angiogenesis-related factors in skeletal muscles of COPD patients: roles of angiopoietin-2.

The role of angiogenesis factors in skeletal muscle dysfunction in patients with chronic obstructive pulmonary disease (COPD) is unknown. The first objective of this study was to assess various pro- and antiangiogenic factor and receptor expressions in the vastus lateralis muscles of control subjects and COPD patients. Preliminary inquiries revealed that angiopoietin-2 (ANGPT2) is overexpressed in limb muscles of COPD patients. ANGPT2 promotes skeletal satellite cell survival and differentiation. Factors that are involved in regulating muscle ANGPT2 production are unknown. The second objective of this study was to evaluate how oxidants and proinflammatory cytokines influence muscle-derived ANGPT2 expression. Angiogenic gene expressions in human vastus lateralis biopsies were quantified with low-density real-time PCR arrays. ANGPT2 mRNA expressions in cultured skeletal myoblasts were quantified in response to proinflammatory cytokine and H2O2 exposure. Ten proangiogenesis genes, including ANGPT2, were significantly upregulated in the vastus lateralis muscles of COPD patients. ANGPT2 mRNA levels correlated negatively with forced expiratory volume in 1 s and positively with muscle wasting. Immunoblotting confirmed that ANGPT2 protein levels were significantly greater in muscles of COPD patients compared with control subjects. ANGPT2 expression was induced by interferon-γ and -ß and by hydrogen peroxide, but not by tumor necrosis factor. We conclude that upregulation of ANGPT2 expression in vastus lateralis muscles of COPD patients is likely due to oxidative stress and represents a positive adaptive response aimed at facilitating myogenesis and angiogenesis.

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-3ß 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.