Mechanisms of exercise-induced improvements in the contractile apparatus of the mammalian myocardium

One of the main outcomes of aerobic endurance exercise training is the improved maximal oxygen uptake, and this is pivotal to the improved work capacity that follows the exercise training. Improved maximal oxygen uptake in turn is at least partly achieved because exercise training increases the ability of the myocardium to produce a greater cardiac output. In healthy subjects, this has been demonstrated repeatedly over many decades. It has recently emerged that this scenario may also be true under conditions of an initial myocardial dysfunction. For instance, myocardial improvements may still be observed after exercise training in post-myocardial infarction heart failure. In both health and disease, it is the changes that occur in the individual cardiomyocytes with respect to their ability to contract that by and large drive the exercise training-induced adaptation to the heart. Here, we review the evidence and the mechanisms by which exercise training induces beneficial changes in the mammalian myocardium, as obtained by means of experimental and clinical studies, and argue that these changes ultimately alter the function of the whole heart and contribute to the changes in whole-body function

Going Offshore: Horseplay, Normalization and Sexual Harassment

On November 7 or 8, Oncale was present when a new galleyhand complained to the Chevron company representative in charge of the Chevron platform about Pippen kissing that galleyhand and Lyons telling that galleyhand that Lyons “loved him” and wanted to “fuck him in his butt.” During a safety meeting the next morning, the Chevron company representative told Lyons and Pippen “not to mess with the galleyhand anymore,” explaining that the galleyhand was “new” and ““green to the field” and that the galleyhand “didn’t know how it was offshore.” Brief for Respondents, Oncale v. Sundowner Offshore Srvs., Inc., 523 U.S. 75 (1998) (No. 96-568), 1997 WL 634147, at *3

Risking Communications Security: Potential Hazards of the Protect America Act

A new US law allows warrantless wiretapping whenever one end of the communication is believed to be outside national borders. This creates serious security risks: danger of exploitation of the system by unauthorized users, danger of criminal misuse by trusted insiders, and danger of misuse by government agents

A New Method for Non-Invasive Estimation of Human Muscle Fiber Type Composition

Background: It has been established that excellence in sports with short and long exercise duration requires a high proportion of fast-twitch (FT) or type-II fibers and slow-twitch (ST) or type-I fibers, respectively. Until today, the muscle biopsy method is still accepted as gold standard to measure muscle fiber type composition. Because of its invasive nature and high sampling variance, it would be useful to develop a non-invasive alternative.status: publishe

Functional overload attenuates plantaris atrophy in tumor-bearing rats

Background Late stage cancer malignancies may result in severe skeletal muscle wasting, fatigue and reduced quality of life. Resistance training may attenuate these derangements in cancer patients, but how this hypertrophic response relates to normal muscle adaptations in healthy subjects is unknown. Here, we determined the effect of resistance training on muscle mass and myosin heavy chain (MHC) isoform composition in plantaris muscles from tumor-bearing (TB) rats. Methods Age- and gender-matched Buffalo rats were used for all studies (n = 6/group). Suspensions of Morris Hepatoma MH7777 cells or normal saline were injected subcutaneously into the dorsum. Six weeks after cell implantation, muscles from TB rats were harvested, weighed and processed for ATP-independent proteasome activity assays. Once tumor-induced atrophy had been established, subgroups of TB rats underwent unilateral, functional overload (FO). Healthy, sham-operated rats served as controls. After six weeks, the extent of plantaris hypertrophy was calculated and MHC isoform compositions were determined by gel electrophoresis. Results Six weeks of tumor growth reduced body mass and the relative masses of gastrocnemius, plantaris, tibialis anterior, extensor digitorum longus, and diaphragm muscles (p ≤ 0.05). Percent reductions in body mass had a strong, negative correlation to final tumor size (r = -0.78). ATP-independent proteasome activity was increased in plantaris muscles from TB rats (p ≤ 0.05). In healthy rats, functional overload (FO) increased plantaris mass ~44% compared to the contralateral control muscle, and increased the relative percentage of MHC type I and decreased the relative percentage of MHC type IIb compared to the sham-operated controls (p ≤ 0.05). Importantly, plantaris mass was increased ~24% in TB-FO rats and adaptations to MHC isoform composition were consistent with normal, resistance-trained muscles. Conclusion Despite significant skeletal muscle derangements due to cancer, muscle retains the capacity to respond normally to hypertrophic stimuli. Specifically, when challenged with functional overload, plantaris muscles from TB rats displayed greater relative mass, increased percentages of MHC type I and decreased percentages of MHC type IIb. Therefore, resistance training paradigms should provide relative morphological and functional benefits to cancer patients suffering from muscle wasting.Published versio

Chronic CaMKII inhibition blunts the cardiac contractile response to exercise training

Activation of the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a critical role modulating cardiac function in both health and disease. Here, we determined the effect of chronic CaMKII inhibition during an exercise training program in healthy mice. CaMKII was inhibited by KN-93 injections. Mice were randomized to the following groups: sham sedentary, sham exercise, KN-93 sedentary, and KN-93 exercise. Cardiorespiratory function was evaluated by ergospirometry during treadmill running, echocardiography, and cardiomyocyte fractional shortening and calcium handling. The results revealed that KN-93 alone had no effect on exercise capacity or fractional shortening. In sham animals, exercise training increased maximal oxygen uptake by 8% (p < 0.05) compared to a 22% (p < 0.05) increase after exercise in KN-93 treated mice (group difference p < 0.01). In contrast, in vivo fractional shortening evaluated by echocardiography improved after exercise in sham animals only: from 25 to 32% (p < 0.02). In inactive mice, KN-93 reduced rates of diastolic cardiomyocyte re-lengthening (by 25%, p < 0.05) as well as Ca2+ transient decay (by 16%, p < 0.05), whereas no such effect was observed after exercise training. KN-93 blunted exercise training response on cardiomyocyte fractional shortening (63% sham vs. 18% KN-93; p < 0.01 and p < 0.05, respectively). These effects could not be solely explained by the Ca2+ transient amplitude, as KN-93 reduced it by 20% (p < 0.05) and response to exercise training was equal (64% sham and 47% KN-93; both p < 0.01). We concluded that chronic CaMKII inhibition increased time to 50% re-lengthening which were recovered by exercise training, but paradoxically led to a greater increase in maximal oxygen uptake compared to sham mice. Thus, the effect of chronic CaMKII inhibition is multifaceted and of a complex nature

Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse

BACKGROUND: The majority of cancer patients experience dramatic weight loss, due to cachexia and consisting of skeletal muscle and fat tissue wasting. Cachexia is a negative prognostic factor, interferes with therapy and worsens the patients' quality of life by affecting muscle function. Mice bearing ectopically-implanted C26 colon carcinoma are widely used as an experimental model of cancer cachexia. As part of the search for novel clinical and basic research applications for this experimental model, we characterized novel cellular and molecular features of C26-bearing mice. METHODS: A fragment of C26 tumor was subcutaneously grafted in isogenic BALB/c mice. The mass growth and proliferation rate of the tumor were analyzed. Histological and cytofluorometric analyses were used to assess cell death, ploidy and differentiation of the tumor cells. The main features of skeletal muscle atrophy, which were highlighted by immunohistochemical and electron microscopy analyses, correlated with biochemical alterations. Muscle force and resistance to fatigue were measured and analyzed as major functional deficits of the cachectic musculature. RESULTS: We found that the C26 tumor, ectopically implanted in mice, is an undifferentiated carcinoma, which should be referred to as such and not as adenocarcinoma, a common misconception. The C26 tumor displays aneuploidy and histological features typical of transformed cells, incorporates BrdU and induces severe weight loss in the host, which is largely caused by muscle wasting. The latter appears to be due to proteasome-mediated protein degradation, which disrupts the sarcomeric structure and muscle fiber-extracellular matrix interactions. A pivotal functional deficit of cachectic muscle consists in increased fatigability, while the reported loss of tetanic force is not statistically significant following normalization for decreased muscle fiber size. CONCLUSIONS: We conclude, on the basis of the definition of cachexia, that ectopically-implanted C26 carcinoma represents a well standardized experimental model for research on cancer cachexia. We wish to point out that scientists using the C26 model to study cancer and those using the same model to study cachexia may be unaware of each other's works because they use different keywords; we present strategies to eliminate this gap and discuss the benefits of such an exchange of knowledge

STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia.Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer.These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood