Heart failure (HF) is known to lead to skeletal muscle atrophy and dysfunction. However, intracellular mechanisms underlying HF-induced myopathy are not fully understood. We hypothesized that HF would increase oxidative stress and ubiquitin-proteasome system (UPS) activation in skeletal muscle of sympathetic hyperactivity mouse model. We also tested the hypothesis that aerobic exercise training (AET) would reestablish UPS activation in mice and human HF. Time-course evaluation of plantaris muscle cross-sectional area, lipid hydroperoxidation, protein carbonylation and chymotrypsin-like proteasome activity was performed in a mouse model of sympathetic hyperactivity-induced HF. At the 7^th month of age, HF mice displayed skeletal muscle atrophy, increased oxidative stress and UPS overactivation. Moderate-intensity AET restored lipid hydroperoxides and carbonylated protein levels paralleled by reduced E3 ligases mRNA levels, and reestablished chymotrypsin-like proteasome activity and plantaris trophicity. In human HF (patients randomized to sedentary or moderate-intensity AET protocol), skeletal muscle chymotrypsin-like proteasome activity was also increased and AET restored it to healthy control subjects’ levels. Collectively, our data provide evidence that AET effectively counteracts redox imbalance and UPS overactivation, preventing skeletal myopathy and exercise intolerance in sympathetic hyperactivity-induced HF in mice. Of particular interest, AET attenuates skeletal muscle proteasome activity paralleled by improved aerobic capacity in HF patients, which is not achieved by drug treatment itself. Altogether these findings strengthen the clinical relevance of AET in the treatment of HF.

It is well known that thyroid hormone affects body composition; however, the effect of the thyroid hormone receptor β (TRβ)-selective thyromimetic GC-1 on this biological feature had not been demonstrated. In the current study, we compared the effects of a 6-week treatment with triiodothyronine (T3; daily injections of 3 or 6 μg/100 g body weight) or GC-1 (equimolar doses) on different metabolic parameters in adult female rats. Whereas all animals gained weight (17–25 g) in a way not basically affected by T3 or GC-1 treatment, only T3 treatment selectively increased food intake (50–70%). Oxygen consumption was significantly and equally increased (50–70%) by T3 and GC-1. Analysis of body composition by dual-energy X-ray absorptiometry (DEXA) revealed that, whereas control animals gained about 80% of fat mass, T3- or GC-1-treated animals lost 70–90 and ~20% respectively. Direct analysis of the carcass showed that T3 treatment promoted a 14–74% decrease in fat content but GC-1 treatment promoted only a 15–23% reduction. The gain in lean mass by DEXA and the carcass protein content were not affected by T3 or GC-1 treatment. However, the mass of individual skeletal muscles was negatively affected by T3 but only barely by GC-1. These findings highlight the potential use of GC-1 for the treatment of obesity and the metabolic syndrome.

Cacy of a moderate-intensity resistance training program combined with vascular occlusion by examining functional capacity, muscle morphology, and changes in the expression of genes related to muscle protein synthesis and proteolysis in a patient with IBM. Methods: A 65-yr-old man with IBM resistant to all proposed treatments underwent resistance training with vascular occlusion for 12 wk. Leg press one-repetition maximum; thigh cross-sectional area; balance, mobility, and muscle function; quality of life; and blood markers of inflammation and muscle damage were assessed at baseline and after the 12-wk program. The messenger RNA (mRNA) expression levels of mechanogrowth factor, mammalian target of rapamycin, atrogin-1, and muscle RING finger-1 were also quantified. Results: After the 12-wk training program, the patient's leg press one-repetition maximum, balance and mobility function, and thigh cross-sectional area increased 15.9%, 60%, and 4.7%, respectively. All Short Form-36 Health Survey Questionnaire subscales demonstrated improvements as well, varying from 18% to 600%. mRNA expression of mechanogrowth factor increased 3.97-fold, whereas that of atrogin-1 decreased 0.62-fold. Muscle RING finger-1 and mammalian target of rapamycin mRNA levels were only slightly altered, 1.18- and 1.28-fold, respectively. Importantly, the exercise did not induce disease flare. Conclusions: We describe a novel, and likely the first, nonpharmacological therapeutic tool that might be able to counteract the muscle atrophy and the declining strength that usually occur in IBM....

The cDNA of an uncoupling protein (UCP) homolog has been cloned from the swallow-tailed hummingbird, Eupetomena macroura. The hummingbird uncoupling protein (HmUCP) cDNA was amplified from pectoral muscle (flight muscle) using RT-PCR and primers for conserved domains of various known UCP homologs. The rapid amplification of cDNA ends (RACE) method was used to complete the cloning of the 5′ and 3′ ends of the open reading frame. The HmUCP coding region contains 915 nucleotides, and the deduced protein sequence consists of 304 amino acids, being ∼72, 70, and 55% identical to human UCP3, UCP2, and UCP1, respectively. The uncoupling activity of this novel protein was characterized in yeast. In this expression system, the 12CA5-tagged HmUCP fusion protein was detected by Western blot in the enriched mitochondrial fraction. Similarly to rat UCP1, HmUCP decreased the mitochondrial membrane potential as measured in whole yeast by uptake of the fluorescent potential-sensitive dye 3′,3-dihexyloxacarbocyanine iodide. The HmUCP mRNA is primarily expressed in skeletal muscle, but high levels can also be detected in heart and liver, as assessed by Northern blot analysis. Lowering the room’s temperature to 12–14°C triggered the cycle torpor/rewarming, typical of hummingbirds. Both in the pectoral muscle and heart, HmUCP mRNA levels were 1.5- to 3.4-fold higher during torpor. In conclusion, this is the first report of an UCP homolog in birds. The data indicate that HmUCP has the potential to function as an UCP and could play a thermogenic role during rewarming.

This study compared four different intensities of a bench press exercise for muscle soreness, creatine kinase activity, interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and prostaglandin E₂ (PGE₂) concentrations in the blood. Thirty-five male Brazilian Army soldiers were randomly assigned to one of five groups: 50% one-repetition maximum (1-RM), 75% 1-RM, 90% 1-RM, 110% 1-RM, and a control group that did not perform the exercise. The total volume (sets × repetitions × load) of the exercise was matched among the exercise groups. Muscle soreness and plasma creatine kinase activity increased markedly (P < 0.05) after exercise, with no significant differences among the groups. Serum PGE₂ concentration also increased markedly (P < 0.05) after exercise, with a significantly (P < 0.05) greater increase in the 110% 1-RM group compared with the other groups. A weak but significant (P < 0.05) correlation was found between peak muscle soreness and peak PGE₂ concentration, but no significant correlation was evident between peak muscle soreness and peak creatine kinase activity, or peak creatine kinase activity and peak PGE₂ concentration. All groups showed no changes in IL-1β, IL-6 or TNF-α. Our results suggest that the intensity of bench press exercise does not affect the magnitude of muscle soreness and blood markers of muscle damage and inflammation.