Reduced Muscle Cross-sectional Area Research Articles

ACVR2B antagonism as a countermeasure to multi-organ perturbations in metastatic colorectal cancer cachexia.

BackgroundAdvanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi‐organ co‐morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC.MethodsNSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham‐operated animals received saline (n = 5–10 per group). Sham and tumour‐bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B.ResultsmHCT116 hosts displayed losses in fat mass ( − 79%, P < 0.0001), bone mass ( − 39%, P < 0.05), and SKM mass (quadriceps: − 22%, P < 0.001), in line with reduced muscle cross‐sectional area ( − 24%, P < 0.01) and plantarflexion force ( − 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: − 16%, P < 0.0001; fractional shortening %: − 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass ( + 238%, P < 0.001), bone mass ( + 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross‐sectional area: + 43%, P < 0.0001) and plantarflexion force ( + 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc.ConclusionsOur metastatic CRC model recapitulates the multi‐systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi‐organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.

Proteomic changes in skeletal muscle of aged rats in response to resistance training.

Sarcopenia is a multifactorial process defined by loss of strength and skeletal muscle mass, which leads to a reduction in muscle cross-sectional area (CSA). Although resistance training (RT) has been indicated as a tool to counteract sarcopenia, the protein profile associated with skeletal muscle adaptations remains to be determined. We investigated the effects of 12 weeks of RT on the skeletal muscle proteome profile and CSA of young and older rats. Twenty-four animals were divided into four groups: young sedentary or trained and older sedentary or trained (six animals per group). A 12-week RT protocol was performed, which consisted of climbing a vertical ladder. The proteins from the gastrocnemius were analysed by LC-ESI-MS/MS. One-hundred and thirty-one proteins were identified, of which 28 were assessed between the groups. Ageing induced an increase in proteins associated with the glycolytic pathway, transport and stress response, which represent crucial mechanisms for muscle adaptation. RT upregulated metabolic enzymes, anti-oxidant activity and transport proteins, besides increasing hypertrophy, regardless of age, suggesting a beneficial adaptation to mitigate age-related sarcopenia. RT reduced muscle atrophy through the regulation of stress response and by increasing proteins related to energy production and transport, which in turn might protect tissue damage arising from exercise and ageing. SIGNIFICANCE OF THE STUDY: Protein abundance levels related to the metabolic process and stress response were increased in the aged muscle. RT proved to be an important intervention capable of inducing significant effects on muscle proteome regardless of ageing, due to upregulation of glycolytic enzymes, and anti-oxidant and transport proteins. This effect could lead to a beneficial adaptation in muscle structure, cellular function and overall homeostasis maintenance. This study contributes to better understanding of the basic biology of ageing and clarifies more profoundly the molecular networks behind physiological adaptations promoted by exercise training. Therefore, the results open new perspectives and insights for studies based on transcriptomics, metabolomics and functional assays.

1943-P: The Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin Can Suppress Muscle Atrophy in Db/Db Mice by Suppressing the Expression of Foxo1

Here we investigated the effect of the sodium glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin on skeletal muscle. Eight-week-old mice were fed a standard diet or the standard diet with added luseogliflozin for 8 weeks. The mice were divided into the following four genotype/dietary groups: Db/m mice without (w/o) SGLT2i, Db/m mice with SGLT2i, Db/Db w/o SGLT2i, and Db/Db with SGLT2i. After the 8-week dietary treatment, we investigated the changes in body weight, glucose tolerance, and muscle in each group. Among the mice with and w/o SGLT2i, the ratio of soleus and plantaris muscle to body weight in the Db/Db mice was significantly lower than that in the Db/m mice. The cross-sectional area of soleus muscle in the Db/Db mice w/o SGLT2i was significantly higher than that in the Db/Db mice with SGLT2i. The expression of foxo1 in soleus muscle of the Db/Db mice was significantly higher than that of the Db/m mice, and the foxo1 expression of the Db/Db mice with SGLT2i was significantly lower than that of the mice w/o SGLT2i. The fluorescence intensity of foxo1 in the Db/Db mice fed SGLT2i was significantly lower than that in the Db/Db mice w/o SGLT2i.The administration of luseogliflozin resulted in the suppression of both the increased foxo1 expression and the reduced muscle cross-sectional area in the soleus muscle of Db/Db mice. Disclosure R. Bamba: None. T. Kimura: None. T. Okamura: None. Y. Hashimoto: Research Support; Self; Asahi Kasei Pharma. T. Osaka: None. T. Senmaru: None. M. Fukui: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Johnson &amp; Johnson, Kyowa Hakko Kirin Co., Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

The sodium-glucose cotransporter 2 inhibitor luseogliflozin can suppress muscle atrophy in Db/Db mice by suppressing the expression of foxo1.

We investigated the effect of the sodium glucose cotransporter-2 inhibitor (SGLT-2i) luseogliflozin on skeletal muscle. Eight-week-old mice were fed a standard diet or the standard diet with added luseogliflozin for 8 weeks. The mice were divided into the following four genotype/dietary groups: Db/m mice without SGLT-2i, Db/m mice with SGLT-2i inhibitor, Db/Db without SGLT-2i, and Db/Db with SGLT-2i. Among the mice with and without SGLT-2i, the ratio of soleus and plantaris muscle to body weight in the Db/Db mice was significantly lower than that in the Db/m mice. The cross-sectional area of soleus muscle in the Db/Db mice without SGLT-2i was significantly higher than that in the Db/Db mice with SGLT-2i. The expression of foxo1 in soleus muscle of the Db/Db mice was significantly higher than that of the Db/m mice, and the foxo1 expression of the Db/Db mice with SGLT-2i was significantly lower than that of the mice without SGLT-2i. The fluorescence intensity of foxo1 in the Db/Db mice fed SGLT-2i was significantly lower than that in the Db/Db mice without SGLT-2i. The administration of luseogliflozin resulted in the suppression of both the increased foxo1 expression and the reduced muscle cross-sectional area in the soleus muscle of Db/Db mice.

PO-064 A potential role of stretch-activated channels in anabolic mechanotransduction in the atrophied rat soleus muscle

Objective Prolonged immobilization or unloading of skeletal muscle causes muscle disuse atrophy, which is characterized by a reduction in muscle cross-sectional area and compromised contractile function. To date, the mechanisms of anabolic mechanotransduction in the atrophied mammalian skeletal muscle remain poorly understood. The aim of the present study was to assess a possible role of stretch-activated ion channels (SAC) in the propagation of a mechanical signal to anabolic signaling and protein synthesis (PS) in an isolated rat soleus muscle following mechanical unloading.&#x0D; Methods The mechanical unloading was performed via hindlimb suspension (HS). Twenty-eight male Wistar rats weighing were randomly assigned to the following 4 groups (n=7/group): 1) vivarium control (C), 2) control + SAC inhibitor (gadolinium) (C+Gd3+), 3) 7-day HS (HS), 4) 7-day HS + SAC inhibitor (HS+Gd3+). Following unloading, an isolated rat soleus was placed in an organ culture medium and subjected to a bout of eccentric contractions (EC). Upon completion of the EC, muscles were collected for Western blot analyses to determine the content of the key anabolic markers. The rate of PS was measured by SUnSET technique.&#x0D; Results EC-induced increase in PS was significantly less in the HS and HS+ Gd3+ groups vs. the C group. There was no statistically significant difference between the HS and HS+ Gd3+ groups in terms of EC-induced increase in muscle PS. A decrease in EC-induced phosphorylation of p70S6K, 4E-BP1, RPS6 and GSK-3beta in the 7-day unloaded soleus treated with SAC inhibitor did not differ from that of the 7-day unloaded soleus without SAC blockade. Thus, the inhibition of SAC with gadolinium did not lead to further decline in EC-induced phosphorylation of the key anabolic markers and muscle PS.&#x0D; Conclusions The results of the study suggest that attenuation of mTORC1-signaling and PS in response to EC in unloaded soleus muscle may be associated with inactivation of SAC. The study was supported by the RFBR grant # 16-34-60055.

Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia.

BackgroundCachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under‐studied in OC due to a limited number of pre‐clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC.MethodsNod SCID gamma mice (n = 6–10) were injected intraperitoneally with 1 × 107 ES‐2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour‐derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL‐6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections.ResultsIn about 2 weeks, ES‐2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES‐2 tumours caused severe cachexia with marked loss of body weight (–12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour‐bearing mice (approximately –35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross‐sectional area (–34%, P < 0.01) and muscle weakness (–50%, P < 0.001). Body composition assessment by dual‐energy X‐ray absorptiometry revealed decreased bone mineral density (–8%, P < 0.01) and bone mineral content (–19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro‐CT imaging of bone morphometry. In the ES‐2 mouse model, cachexia was also associated with high tumour‐derived IL‐6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho‐STAT3 (+274%, P < 0.001), reduced phospho‐AKT (–44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES‐2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (–16%, P < 0.001), consistent with elevated phospho‐STAT3 (+1.4‐fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL‐6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size.ConclusionsOur results suggest that the development of ES‐2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL‐6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.

Differential Effects of 2 Rehabilitation Programs Following Anterior Cruciate Ligament Reconstruction.

The muscular function restoration related to the type of physical rehabilitation followed after anterior cruciate ligament reconstruction (ACLR) using autologous hamstring tendon graft in terms of strength and cross-sectional area (CSA) remain controversial. To analyze the CSA and force output of quadriceps and hamstring muscles in subjects following either an Objective Criteria-Based Rehabilitation (OCBR) algorithm or the usual care (UCR) for ACL rehabilitation in Spain, before and 1 year after undergoing an ACLR. Longitudinal clinical double-blinded randomized controlled trial. Sports-medicine research center. 40 recreational athletes (30 male, 10 female [24 ± 6.9 y, 176.55 ± 6.6 cm, 73.58 ± 12.3 kg]). Both groups conducted differentiated rehabilitation procedures after ACLR. Those belonging to OCBR group were guided in their recovery according to the current evidence-based principles. UCR group followed the national conventional approach for ACL rehabilitation. Concentric isokinetic knee joint flexor-extension torque assessments at 180°/s and Magnetic Resonance Imaging (MRI) evaluations were performed before and 12 months after ACLR. Anatomical muscle CSA (mm2) was assessed, in Quadriceps, Biceps femoris, Semitendinous, Semimembranosus, and Gracilis muscles at 50% and 70% femur length. Reduced muscle CSA was observed in both treatment groups for Semitendinosus and Gracilis 1 year after ACLR. At 1-year follow-up, subjects allocated to the OCBR demonstrated greater knee flexor and extensor peak torque values in their reconstructed limbs in comparison with patients treated by UCR. Objective atrophy of Semitendinosus and Gracilis muscles related to surgical ACLR was found to persist in both rehabilitation groups. However, OCBR after ACLR lead to substantial gains on maximal knee flexor strength and ensured more symmetrical anterior-posterior laxity levels at the knee joint.

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia.

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification.

Ageing-induced Reduction In Muscle Cross-sectional Area Is Associated With Serum C1q Concentration

Ageing-induced Reduction In Muscle Cross-sectional Area Is Associated With Serum C1q Concentration

Structural alterations of skeletal muscle in copd

Background: Chronic obstructive pulmonary disease (COPD) is a respiratory disease associated with a systemic inflammatory response. Peripheral muscle dysfunction has been well characterized in individuals with COPD and results from a complex interaction between systemic and local factors.Objective: In this narrative review, we will describe muscle wasting in people with COPD, the associated structural changes, muscle regenerative capacity and possible mechanisms for muscle wasting. We will also discuss how structural changes relate to impaired muscle function and mobility in people with COPD.Key Observations: Approximately 30–40% of individuals with COPD experience muscle mass depletion. Furthermore, muscle atrophy is a predictor of physical function and mortality in this population. Associated structural changes include a decreased proportion and size of type-I fibers, reduced oxidative capacity and mitochondrial density mainly in the quadriceps. Observations related to impaired muscle regenerative capacity in individuals with COPD include a lower proportion of central nuclei in the presence or absence of muscle atrophy and decreased maximal telomere length, which has been correlated with reduced muscle cross-sectional area. Potential mechanisms for muscle wasting in COPD may include excessive production of reactive oxygen species (ROS), altered amino acid metabolism and lower expression of peroxisome proliferator-activated receptors-gamma-coactivator 1-alpha mRNA. Despite a moderate relationship between muscle atrophy and function, impairments in oxidative metabolism only seems weakly related to muscle function.Conclusion: This review article demonstrates the cellular modifications in the peripheral muscle of people with COPD and describes the evidence of its relationship to muscle function. Future research will focus on rehabilitation strategies to improve muscle wasting and maximize function.

Bone mass and quality in patients with juvenile idiopathic arthritis: longitudinal evaluation of bone-mass determinants by using dual-energy x-ray absorptiometry, peripheral quantitative computed tomography, and quantitative ultrasonography

IntroductionOur objective was to evaluate longitudinally the main bone-mass and quality predictors in young juvenile idiopathic arthritis (JIA) patients by using lumbar spine dual-energy X-ray absorptiometry (DXA) scan, radius peripheral quantitative computed tomography (pQCT), and phalangeal quantitative ultrasonography (QUS) at the same time.MethodsIn total, 245 patients (172 females, 73 males; median age, 15.6 years: 148 oligoarticular, 55 polyarticular, 20 systemic, and 22 enthesitis-related-arthritis (ERA) onset) entered the study. Of these, 166 patients were evaluated longitudinally. Data were compared with two age- and sex-matched control groups.ResultsIn comparison with controls, JIA patients, but not with ERA, had a reduced spine bone-mineral apparent density (BMAD) standard deviation score (P < 0.001) and musculoskeletal deficits, with significantly lower levels of trabecular bone mineral density (TrabBMD) (P < 0.0001), muscle cross-sectional area (CSA) (P < 0.005), and density-weighted polar section modulus (SSIp) (P < 0.05). In contrast, JIA showed fat CSA significantly higher than controls (P < 0.0001). Finally, JIA patients had a significant reduced amplitude-dependent speed of sound (AD-SoS) (P < 0.001), and QUS z score (P < 0.005).Longitudinally, we did not find any difference in all JIA patients in comparison with baseline, except for the SSIp value that normalized. Analyzing the treatments, a significant negative correlation among spine BMAD values, TrabBMD, AD-SoS, and systemic and/or intraarticular corticosteroids, and a positive correlation among TNF-α-blocking agents and spine BMAD, TrabBMD, and AD-SoS were observed.ConclusionsJIA patients have a low bone mass that, after a first increase due to the therapy, does not reach the normal condition over time. The pronounced bone deficits in JIA are greater than would be expected because of reduction in muscle cross-sectional area. Thus, bone alterations in JIA likely represent a mixed defect of bone accrual and lower muscle forces.

Deletion of Growth Hormone Receptors in Postnatal Skeletal Muscle of Male Mice Does Not Alter Muscle Mass and Response to Pathological Injury

In this study, we investigated whether loss of GH receptor (GHR) signaling in postnatal skeletal muscle alters muscle mass and regenerative ability in adult mice and whether this was dependent on IGF-1 receptor (IGF-1R) signaling. To do so, we used mouse models with skeletal muscle-specific loss of GHR signaling (mGHRKO), IGF-1R and insulin receptor signaling (MKR), or both GHR and IGF-1R/insulin receptor signaling (mGHRKO/MKR). We did not find a reduction in muscle cross-sectional area, fiber type composition, or response to pathological muscle injury in male mGHRKO and mGHRKO/MKR mice when compared with control and MKR mice, respectively. This could potentially be explained by unchanged skeletal muscle Igf-1 expression in mGHRKO and mGHRKO/MKR mice relative to control and MKR mice, respectively. Furthermore, MKR and mGHRKO/MKR mice, but not mGHRKO mice, demonstrated reduced fiber fusion after cardiotoxin injection, suggesting that IGF-1, and not GH, promotes fiber fusion in adult mice. In summary, our data suggest that GHR signaling in postnatal skeletal muscle does not play a significant role in regulating muscle mass or muscle regeneration. Additionally, in our model, muscle Igf-1 expression is not dependent on GHR signaling in postnatal skeletal muscle.

Evaluation of Change in Muscle Activity as a Result of Posterior Lumbar Spine Surgery Using a Dynamic Modeling System

A commercially available musculoskeletal model of the lumbar spine was modified to study the change in muscle activation as a result of posterior lumbar surgery at the L3-L4 and L4-L5 segments. To evaluate how graded resection of the lumbar paraspinal muscles as a result of posterior lumbar surgery affects muscle activity for a variety of movement tasks. Several in vivo studies compare the change in functional outcome of the paraspinal muscles following surgery. However, due to limitations that exist with current in vivo methods no study to date has been able to quantitatively examine how the function of individual muscles in the lumbar spine change in response to different levels of injury. A multibody dynamic musculoskeletal model of the lumbar spine was modified to measure muscle activity using a parametric examination of change in the cross-sectional area of muscles affected by posterior lumbar surgery. This study shows that the reduction in muscle cross-sectional area as a result of posterior lumbar surgery at L3-L4 and L4-L5 results in a change in trunk muscle activity where the greatest change occurs during axial rotation and lateral bending. The results suggest that preservation of the posterior paraspinal musculature results in greater preservation of the normal muscle activity than traditional open techniques. Preservation of the paraspinal musculature associated with minimally invasive surgical approaches to the lumbar better preserve postoperative muscle activity. This study suggests that there is a positive correlation between the reduction of paraspinal muscle cross-sectional area following posterior lumbar spine surgery and the alteration in trunk muscle activity.

Regulatory mechanism of smooth muscle contraction studied with gelsolin-treated strips of taenia caeci in guinea pig

The potential roles of the regulatory proteins actin, tropomyosin (Tm), and caldesmon (CaD), i.e., the components of the thin filament, in smooth muscle have been extensively studied in several types of smooth muscles. However, controversy remains on the putative physiological significance of these proteins. In this study, we intended to determine the functional roles of Tm and CaD in the regulation of smooth muscle contraction by using a reconstitution system of the thin filaments. At appropriate conditions, the thin (actin) filaments within skinned smooth muscle strips of taenia caeci in guinea pigs could be selectively removed by an actin-severing protein, gelsolin, without irreversible damage to the contractile apparatus, and then the thin filaments were reconstituted with purified components of thin filaments, i.e., actin, Tm, and CaD. We found that the structural remodeling of actin filaments or thin filaments was functionally linked to the Ca(2+)-induced force development and reduction in muscle cross-sectional area (CSA). That is, after the reconstitution of the gelsolin-treated skinned smooth muscle strips with pure actin, the Ca(2+)-dependent force development was partially restored, but the Ca(2+)-induced reduction in CSA occurred once. In contrast, the reconstitution with actin, followed by Tm and CaD, restored not only the force generation but also both its Ca(2+) sensitivity and the reversible Ca(2+)-dependent reduction in CSA. We confirmed that both removal of the thin filaments by gelsolin treatment and reconstitution of the actin (thin) filaments with Tm and CaD caused no significant changes in the level of myosin regulatory light chain phosphorylation. We thus conclude that Tm and CaD are necessary for the full regulation of smooth muscle contraction in addition to the other regulatory systems, including the myosin-linked one.

Prolonged aestivation causes little change in skeletal muscle morphology or contractile performance in the anuran Cyclorana aloboguttata

Prolonged immobilisation or unloading of skeletal muscle causes muscle disuse atrophy that is characterised by a reduction in muscle cross-sectional area and compromised locomotory function. Animals that enter seasonal dormancy, such as hibernators and aestivators, exhibit a decline in metabolic and locomotor activity that is correlated with seasonal fluctuations in temperature and resource availability. As such, hibernators and aestivators provide a fascinating natural model for investigating muscle atrophy associated with disuse (see review by Hudson and Franklin, 2002). Previous research has also indicated that aerobic muscles should be more susceptible to muscle disuse atrophy than glycolytic muscles as there is a greater change in daily activity. We investigated the effect of aestivation on ileofibularis (relatively slow twitch) and sartorius (relatively fast twitch) muscle morphology and contractile function in C. alboguttata over a longer, more ecologically relevant time-frame of nine months. We found that whole muscle mass, muscle cross-sectional area, fibre number and proportions of fibre types remained unchanged after prolonged disuse. There were significant reductions in ileofibularis fibre cross-sectional area (> 35%) and sartorius fibre density (44%) and significant slowing of isometric kinetics. However, the work loop power output of both muscles from nine-month aestivating C. alboguttata were maintained at control levels. The results from this study strongly support the supposition that C. alboguttata is able to inhibit the effects of atrophy during disuse in both sartorius and ileofibularis muscles.

Getting the jump on skeletal muscle disuse atrophy: preservation of contractile performance in aestivatingCyclorana alboguttata(Günther 1867)

Prolonged immobilisation or unloading of skeletal muscle causes muscle disuse atrophy, which is characterised by a reduction in muscle cross-sectional area and compromised locomotory function. Animals that enter seasonal dormancy, such as hibernators and aestivators, provide an interesting model for investigating atrophy associated with disuse. Previous research on the amphibian aestivator Cyclorana alboguttata (Günther 1867) demonstrated an absence of muscle disuse atrophy after 3 months of aestivation, as measured by gastrocnemius muscle contractile properties and locomotor performance. In this study, we aimed to investigate the effect of aestivation on iliofibularis and sartorius muscle morphology and contractile function of C. alboguttata over a longer, more ecologically relevant time-frame of 9 months. We found that whole muscle mass, muscle cross-sectional area, fibre number and proportions of fibre types remained unchanged after prolonged disuse. There was a significant reduction in iliofibularis fibre cross-sectional area (declined by 36% for oxidative fibre area and 39% for glycolytic fibre area) and sartorius fibre density (declined by 44%). Prolonged aestivation had little effect on the isometric properties of the skeletal muscle of C. alboguttata. There was a significant reduction in the isometric contraction times of the relatively slow-twitch iliofibularis muscle, suggesting that the muscle was becoming slower after 9 months of aestivation (time to peak twitch increased by 25%, time from peak twitch to half relaxation increased by 34% and time from last stimulus to half tetanus relation increased by 20%). However, the results of the work-loop analysis clearly demonstrate that, despite changes to muscle morphology and isometric kinetics, the overall contractile performance and power output levels of muscles from 9-month aestivating C. alboguttata are maintained at control levels.

Reduced muscle radiological density, cross-sectional area, and strength of major hip and knee muscles in 22 patients with hip osteoarthritis

Background Patients with hip osteoarthritis (OA) typically suffer joint pain, and often experience muscular weakness. We hypothesized that substantial atrophy would manifest in multiple muscle groups along the affected limb, resulting in severe muscle dysfunction.Patients and methods We assessed 22 elderly patients with unilateral OA for maximal voluntary isometric strength of hip and knee muscles using a dynamometer that was developed for the purpose. Cross-sectional area (CSA) and radiological density (RD; in Hounsfield units: HU) of hip and knee muscles were assessed using CT. We determined SF-36, HHS, and EQ-5D.Results Hip extension, flexion, adduction, abduction, and knee extension strength were reduced (11– 29%; p < 0.01) in the OA limb relative to the healthy limb. Muscle CSA of hip extensors, flexors, adductors, knee extensors and flexors, but not hip abductors, was reduced (11–19%; p < 0.01) in the OA limb, where RD of all muscle groups except hip flexors was reduced (5–15 HU; p < 0.01). The clinical scores confirmed impairment.Interpretation Major muscles functioning around the hip and knee showed substantial loss of strength and mass, which contributes to the reduced ambulatory capacity of OA patients. Reduced muscle CSA could not fully explain the loss in strength. Infiltration with fat or other non-contractile components, as indicated by a reduced RD, in OA limb muscles was substantial.

Impacting patient-centred outcomes in COPD: deconditioning

Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from exercise intolerance, leading to a reduced ability to participate in activities of daily life and, therefore, to a reduced health-related quality of life (HRQoL). An important determinant of exercise intolerance is the loss of muscle mass. Although the mechanism for loss of muscle function is multi-factorial, deconditioning appears to play a primary role in many patients. COPD patients often have decreased fat-free mass compared with healthy counterparts and reduced muscle cross-sectional area. It seems, then, that a cycle of decline often characterises COPD, in which inactivity results in muscle weakness, which in turn acts as a further deterrent to exercise. Such deconditioning can be reversed by pulmonary rehabilitation, leading to significant improvements in exercise tolerance and HRQoL. Recent research suggests that the effectiveness of pulmonary rehabilitation can be amplified with concomitant administration of tiotropium (a long-acting bronchodilator) or supplemental oxygen. This suggests that facilitating higher training work-rates can enhance the anabolic effects of training. Patients should be encouraged to maintain activity levels in the follow-up period after training, in order to retain the benefits of rehabilitation.

A maternal cafeteria diet during gestation and lactation promotes adiposity and impairs skeletal muscle development and metabolism in rat offspring at weaning.

We examined the effects of a maternal cafeteria diet on skeletal muscle and adipose tissue development in the offspring at weaning. Rats born to mothers fed the cafeteria diet either during gestation alone or during both gestation and lactation exhibited a 25% reduction in muscle cross-sectional area with approximately 20% fewer fibres compared with pups fed a balanced chow diet. Maintaining the cafeteria diet during lactation increased intramuscular lipid content and fat pad weights characterized by adipocyte hypertrophy but not hyperplasia. These pups also had elevated muscle IGF-1, IGF-1 receptor, and PPARgamma mRNA levels, which may indicate an attempt to maintain normal insulin sensitivity. The increased adiposity and elevated IGF-1, IGF-1 receptor and PPARgamma mRNAs were not seen in the pups rehabilitated to the balanced diet during lactation. However, these pups exhibited reduced muscle cell proliferation (PCNA) with reduced insulin receptor and a trend towards reduced glucose transporter (GLUT)-4 mRNAs when compared with pups fed a balanced chow diet, indicating possible alterations in glucose uptake by muscle tissue. Therefore, rats born to mothers fed a cafeteria diet during gestation alone or during both gestation and lactation exhibited impaired skeletal muscle development and metabolic disorders normally associated with insulin resistance as early as the weaning stage.