Search

Sarcopenia is a major comorbidity in chronic obstructive pulmonary (COPD). Whether deficient muscle repair mechanisms and regeneration exist in the vastus lateralis (VL) of sarcopenic COPD remains debatable. In the VL of control subjects and severe COPD patients with/without sarcopenia, satellite cells (SCs) were identified (immunofluorescence, specific antibodies, anti‐Pax‐7, and anti‐Myf‐5): activated (Pax‐7+/Myf‐5+), quiescent/regenerative potential (Pax‐7+/Myf‐5‐), and total SCs, nuclear activation (terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling [TUNEL]), and muscle fiber type (morphometry and slow‐ and fast‐twitch, and hybrid fibers), muscle damage (hematoxylin‐eosin staining), muscle regeneration markers (Pax‐7, Myf‐5, myogenin, and MyoD), and myostatin levels were identified. Compared to controls, in VL of sarcopenic COPD patients, myostatin content, activated SCs, hybrid fiber proportions, TUNEL‐positive cells, internal nuclei, and muscle damage significantly increased, while quadriceps muscle strength, numbers of Pax‐7+/Myf‐5‐ and slow‐ and fast‐twitch, and hybrid myofiber areas decreased. In the VL of sarcopenic and nonsarcopenic patients, TUNEL‐positive cells were greater, whereas muscle regeneration marker expression was lower than in controls. In VL of severe COPD patients regardless of the sarcopenia level, the muscle regeneration process is triggered as identified by SC activation and increased internal nuclei. Nonetheless, a lower regenerative potential along with significant alterations in muscle phenotype and damage, and increased myostatin were prominently seen in sarcopenic COPD. [ABSTRACT FROM AUTHOR]

Impaired muscle strength and mass (sarcopenia) are common in patients with respiratory cachexia, namely chronic obstructive pulmonary disease (COPD) and in lung cancer (LC)‐cachexia. Misfolded/unfolded proteins in endoplasmic reticulum (ER) induce the compensatory unfolded protein response (UPR). Expression of ER stress and UPR markers may be differentially upregulated in vastus lateralis (VL) of patients with respiratory sarcopenia associated with either a chronic condition (COPD) or subacute (LC)‐cachexia. In VL specimens from 40 COPD patients (n = 21, sarcopenic, fat‐free mass index [FFMI] 16 kg/m2 and n = 19, nonsarcopenic, FFMI 18 kg/m2), 13 patients with LC‐cachexia (FFMI 17 kg/m2), and 19 healthy controls (FFMI 19 kg/m 2), expression markers of ER stress, UPR (protein kinase‐like ER kinase [PERK], activating transcription factor [ATF] 6, and inositol‐requiring enzyme [IRE] 1‐α), oxidative stress, autophagy, proteolysis, and apoptosis (reverse transcription polymerase chain reaction and immunoblotting), and fiber atrophy (histology) were assessed. Atrophy and muscle wasting and weakness were seen in both groups of sarcopenic patients. Compared to healthy controls, in muscles of LC‐cachexia patients, expression of ER stress markers and UPR (three arms) was significantly upregulated, while in sarcopenic COPD, expression of a few ER stress markers and IRE1‐α arm was upregulated. ER stress and an exaggerated UPR were observed in the VL muscle of patients with respiratory sarcopenia. The three branches of UPR were similarly upregulated in muscles of cancer cachectic patients, whereas in sarcopenic COPD patients, only IRE1 was upregulated. The differential profile of muscle UPR in chronic and subacute respiratory conditions offers a niche for the design of specific novel therapeutic approaches. Endoplasmic reticulum (ER) stress and an exaggerated unfolded protein response (UPR) were observed in the vastus lateralis (VL) muscle of patients with respiratory sarcopenia and cachexia, particularly in those with lung cancer (LC). The three branches of UPR were similarly upregulated in muscles of cancer cachectic patients, whereas in the sarcopenic chronic obstructive pulmonary disease (COPD) patients, inositol‐requiring enzyme (IRE) 1 arm was mostly upregulated in their VL. The differential expression profile of ER stress and UPR markers observed in chronic and acute respiratory diseases offers a niche for the design of novel customized therapeutic approaches which may encompass exercise training along with pharmacological strategies purported to boost ER function. [ABSTRACT FROM AUTHOR]

Skeletal muscle dysfunction and atrophy are characteristic features accompanying chronic conditions. Epigenetic events regulate muscle mass and function maintenance. We hypothesized that the pattern of epigenetic events (muscle-enriched microRNAs and histone acetylation) and acetylation of transcription factors known to signal muscle wasting may differ between early- and late-time points in skeletal muscles of mice exposed to hindlimb immobilization (I) and recovery following I. Body and muscle weights, grip strength, muscle-enriched microRNAs, histone deacetylases (HDACs), acetylation of proteins, histones, and transcription factors (TF), myogenic TF factors, and muscle phenotype were assessed in gastrocnemius of mice exposed to periods (1, 2, 3, 7, 15, and 30 days, I groups) of hindlimb immobilization, and in those exposed to reloading for different periods of time (1, 3, 7, 15, and 30 days, R groups) following 7-day immobilization. Compared to non-immobilized controls, muscle weight, limb strength, microRNAs, especially miR-486, SIRT1 levels, and slow- and fast-twitch cross-sectional areas were decreased in mice of I groups, whereas Pax7 and acetylated FoxO1 and FoxO3 levels were increased. Muscle reloading following splint removal improved muscle mass loss, strength, and fiber atrophy, by increasing microRNAs, particularly miR-486, and SIRT1 content, while decreasing acetylated FoxO1 and FoxO3 levels. In this mouse model of disuse muscle atrophy, muscle-enriched microRNAs, especially miR-486, through Pax7 regulation delayed muscle cell differentiation following unloading of gastrocnemius muscle. Acetylation of FoxO1 and 3 seemed to drive muscle mass loss and atrophy, while deacetylation of these factors through SIRT1 would enable the muscle fibers to regenerate. J. Cell. Physiol. 232: 1415-1427, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We hypothesized that inflammatory events and reactive oxygen species (ROS) production may be differentially expressed in respiratory and limb muscles, and blood of a chronic intermittent hypoxia (CIH) experimental model and that antioxidants and TNF-alpha blockade may influence those events. In blood, diaphragm, and gastrocnemius of rats non-invasively exposed to CIH (10% hypoxia, 2 h/day, 14 consecutive days) with/without concomitant treatment with either anti-TNF-alpha antibody (infliximab) or N-acetyl cysteine (NAC), inflammatory cytokines, superoxide anion production, muscle structural abnormalities, and fiber-type composition were assessed. Compared to non-exposed controls, in CIH-exposed rats, body weight gain was reduced, TNF-alpha, IL-1beta, IL-6, and interferon-gamma levels were increased in diaphragm, TNF-alpha, and IL-1 beta plasma levels were greater, systemic and muscle superoxide anion production was higher, diaphragm and gastrocnemius inflammatory cells and internal nuclei were higher, and muscle fiber-type and morphometry remained unmodified. CIH rats treated with infliximab further increased TNF-alpha, IL-1beta, IL-6, and interferon-gamma diaphragm levels, whereas NAC induced a reduction only in TNF-alpha and IL-1beta levels in diaphragm and plasma. Infliximab and NAC elicited a significant decline in superoxide anion production in diaphragm, gastrocnemius, and plasma, while inducing a further increase in inflammatory cells and internal nuclei in both muscles. Proinflammatory cytokines are differentially expressed in respiratory and limb muscles and plasma of CIH-exposed rats, while superoxide anion production increased in both muscle types and blood. Infliximab and NAC exerted different effects. These findings may help understand the biology underlying CIH in skeletal muscles and blood of patients with chronic respiratory diseases. J. Cell. Physiol. 232: 1165-1175, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]