Kristen A. Baltgalvis

Interleukin 6 as a Key Regulator of Muscle Mass during Cachexia

Interleukin 6 (IL-6) has received significant attention for its regulatory role in muscle wasting during cachexia. This review examines the role of circulating IL-6 for decreasing muscle mass during cancer and emphasizes some of the indirect actions of IL-6 that may cause muscle wasting.

Hormone Therapy and Skeletal Muscle Strength: A Meta-Analysis

BACKGROUND Our objective was to perform a systematic review and meta-analysis of the research literature that compared muscle strength in postmenopausal women who were and were not on estrogen-based hormone therapy (HT). METHODS Twenty-three relevant studies were found. Effect sizes (ESs) were calculated as the standardized mean difference, and meta-analyses were completed using a random effects model. RESULTS HT was found to result in a small beneficial effect on muscle strength in postmenopausal women (overall ES = 0.23; p = .003) that equated to an approximately 5% greater strength for women on HT. Among the 23 studies, various muscle groups were assessed for strength, and those that benefitted the most were the thumb adductors (ES = 1.14; p < .001). Ten studies that compared muscle strength in rodents that were and were not estradiol deficient were also analyzed. The ES for absolute strength was moderate but not statistically significant (ES = 0.44; p = .12), whereas estradiol had a large effect on strength normalized to muscle size (ES = 0.66; p = .03). CONCLUSION Overall, estrogen-based treatments were found to beneficially affect strength.

Estrogen Regulates Estrogen Receptors and Antioxidant Gene Expression in Mouse Skeletal Muscle

Background Estrogens are associated with the loss of skeletal muscle strength in women with age. Ovarian hormone removal by ovariectomy in mice leads to a loss of muscle strength, which is reversed with 17β-estradiol replacement. Aging is also associated with an increase in antioxidant stress, and estrogens can improve antioxidant status via their interaction with estrogen receptors (ER) to regulate antioxidant gene expression. The purpose of this study was to determine if ER and antioxidant gene expression in skeletal muscle are responsive to changes in circulating estradiol, and if ERs regulate antioxidant gene expression in this tissue. Methodology/Principal Findings Adult C57BL/6 mice underwent ovariectomies or sham surgeries to remove circulating estrogens. These mice were implanted with placebo or 17β-estradiol pellets acutely or chronically. A separate experiment examined mice that received weekly injections of Faslodex to chronically block ERs. Skeletal muscles were analyzed for expression of ER genes and proteins and antioxidant genes. ERα was the most abundant, followed by Gper and ERβ in both soleus and EDL muscles. The loss of estrogens through ovariectomy induced ERα gene and protein expression in the soleus, EDL, and TA muscles at both the acute and chronic time points. Gpx3 mRNA was also induced both acutely and chronically in all 3 muscles in mice receiving 17β-estradiol. When ERs were blocked using Faslodex, Gpx3 mRNA was downregulated in the soleus muscle, but not the EDL and TA muscles. Conclusions/Significance These data suggest that Gpx3 and ERα gene expression are sensitive to circulating estrogens in skeletal muscle. ERs may regulate Gpx3 gene expression in the soleus muscle, but skeletal muscle regulation of Gpx3 via ERs is dependent upon muscle type. Further work is needed to determine the indirect effects of estrogen and ERα on Gpx3 expression in skeletal muscle, and their importance in the aging process.

Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice

James Ervasti and colleagues show that injection of a truncated form of utrophin transduced all tissues examined, integrated with members of the dystrophin complex, and reduced serum levels of creatine kinase in a mouse model of muscular dystrophy.

Muscle oxidative capacity during IL-6-dependent cancer cachexia

Many diseases are associated with catabolic conditions that induce skeletal muscle wasting. These various catabolic states may have similar and distinct mechanisms for inducing muscle protein loss. Mechanisms related to muscle wasting may also be related to muscle metabolism since glycolytic muscle fibers have greater wasting susceptibility with several diseases. The purpose of this study was to determine the relationship between muscle oxidative capacity and muscle mass loss in red and white hindlimb muscles during cancer cachexia development in the Apc(Min/+) mouse. Gastrocnemius and soleus muscles were excised from Apc(Min/+) mice at 20 wk of age. The gastrocnemius muscle was partitioned into red and white portions. Body mass (-20%), gastrocnemius muscle mass (-41%), soleus muscle mass (-34%), and epididymal fat pad (-100%) were significantly reduced in severely cachectic mice (n = 8) compared with mildly cachectic mice (n = 6). Circulating IL-6 was fivefold higher in severely cachectic mice. Cachexia significantly reduced the mitochondrial DNA-to-nuclear DNA ratio in both red and white portions of the gastrocnemius. Cytochrome c and cytochrome-c oxidase complex subunit IV (Cox IV) protein were reduced in all three muscles with severe cachexia. Changes in muscle oxidative capacity were not associated with altered myosin heavy chain expression. PGC-1α expression was suppressed by cachexia in the red and white gastrocnemius and soleus muscles. Cachexia reduced Mfn1 and Mfn2 mRNA expression and markers of oxidative stress, while Fis1 mRNA was increased by cachexia in all muscle types. Muscle oxidative capacity, mitochondria dynamics, and markers of oxidative stress are reduced in both oxidative and glycolytic muscle with severe wasting that is associated with increased circulating IL-6 levels.

Adaptive and nonadaptive responses to voluntary wheel running by mdx mice

The purpose of this study was to determine the extent to which hindlimb muscles of mdx mice adapt to a voluntary endurance type of exercise. mdx and C57BL mice engaged in 8 weeks of wheel running or maintained normal cage activities. Beneficial adaptations that occurred in mdx mice included changes in muscle mass, fiber size, and fiber types based on myosin heavy chain (MHC) isoform expression. These adaptations occurred without increases in fiber central nuclei and embryonic MHC expression. An undesirable outcome, however, was that muscle mitochondrial enzyme activities did not improve with exercise in mdx mice as they did in C57BL mice. Cellular remodeling of dystrophic muscle following exercise has not been studied adequately. In this study we found that some, but not all, of the expected adaptations occurred in mdx mouse muscle. We must better understand these (non)adaptations in order to inform individuals with DMD about the benefits of exercise. Muscle Nerve 38: 1290–1303, 2008

Mechanisms behind estrogen's beneficial effect on muscle strength in females.

Muscle weakness ensues when serum testosterone declines with age in men. Testosterones female counterpart, estrogen, also has been implicated in age-related strength loss, but these results are less conclusive. Our working hypothesis is that estrogens do benefit muscle strength, and that the underlying mechanism involves estrogen receptors to improve muscle quality more so than quantity.

The effect of exercise on IL-6-induced cachexia in the Apc ( Min/+) mouse.

BackgroundCachexia involves unintentional body weight loss including diminished muscle and adipose tissue mass and is associated with an underlying disease. Systemic overexpression of IL-6 accelerates cachexia in the ApcMin/+ mouse, but does not induce wasting in control C57BL/6 mice. With many chronic diseases, chronic inflammation and metabolic dysfunction can be improved with moderate exercise. A direct effect of regular moderate exercise on the prevention of IL-6-induced cachexia in the ApcMin/+ mouse has not been investigated. The purpose of this study was to assess the effects of exercise on the development of cachexia in the ApcMin/+ mouse.MethodsMice were randomly assigned to moderate treadmill exercise (18 m/min, 1 h, 6 days/week, 5% grade) or cage control (CC) groups from 6 to 14 weeks of age. At 12 weeks of age, mice were electroporated with either IL-6-containing or control plasmid into the quadriceps muscle. Mice were killed after 2 weeks of systemic IL-6 overexpression or control treatment.ResultsIL-6 overexpression induced an 8% loss in body weight in CC mice, which was significantly attenuated by exercise. IL-6 overexpression in CC mice increased fasting insulin and triglyceride levels, which were normalized by exercise, and associated with increased oxidative capacity, an induction of AKT signaling, and a repression of AMPK signaling in muscle. These exercise-induced changes occurred despite elevated inflammatory signaling in skeletal muscle.ConclusionWe conclude that moderate-intensity exercise can attenuate IL-6-dependent cachexia in ApcMin/+ mice, independent of changes in IL-6 concentration and muscle inflammatory signaling. The exercise effect was associated with improved insulin sensitivity and improved energy status in the muscle.

Effects of prednisolone on skeletal muscle contractility in mdx mice.

Current treatment for Duchenne muscular dystrophy (DMD) is chronic administration of the glucocorticoid prednisolone. Prednisolone improves muscle strength in boys with DMD, but the mechanism is unknown. The purpose of this study was to determine how prednisolone improves muscle strength by examining muscle contractility in dystrophic mice over time and in conjunction with eccentric injury. Mdx mice began receiving prednisolone (n = 23) or placebo (n = 16) at 5 weeks of age. Eight weeks of prednisolone increased specific force of the extensor digitorum longus muscle 26%, but other parameters of contractility were not affected. Prednisolone also improved the histological appearance of muscle by decreasing the number of centrally nucleated fibers. Prednisolone treatment did not affect force loss during eccentric contractions or recovery of force following injury. These data are of clinical relevance, because the increase in muscle strength in boys with DMD taking prednisolone does not appear to occur via the same mechanism in dystrophic mice. Muscle Nerve, 2009

The Interaction of a High-Fat Diet and Regular Moderate Intensity Exercise on Intestinal Polyp Development in ApcMin/+ Mice

Diet and exercise are two environmental factors that can alter colon cancer risk. The purpose of this study was to determine if regular moderate-intensity treadmill exercise training could attenuate polyp formation in ApcMin/+ mice fed the Western-style diet. Four-week-old male ApcMin/+ mice (n = 12 per group) were assigned to AIN-76A Control, AIN-76A Exercise, Western Control, or Western Exercise treatment groups. Mice were weaned to these diets and either subjected to regular moderate-intensity treadmill exercise (18 m/min, 60 min/d, 6 d/wk) or remained sedentary for 6 weeks. Mice fed the Western-style diet consumed ∼14% more calories and had 42% more epididymal fat compared with mice fed the AIN-76A diet. Exercise had no effect on fat pad mass with either diet treatment. Exercise reduced total intestinal polyp number by 50% and the number of large polyps (>1 mm diameter) by 67% in AIN-76A–fed mice. The Western-style diet increased polyp number by 75% when compared with AIN-76A–fed mice, but exercise did not decrease polyp number or alter polyp size in mice fed the Western-style diet. Markers of systemic inflammation and immune system function were improved with exercise in mice fed the AIN-76A diet. Mice fed the Western-style diet showed more inflammation and immunosuppression, which were not completely ameliorated by exercise. These data suggest that the induction of adiposity, inflammation, and immunosuppression by the Western-style diet may compromise the beneficial effect of moderate-intensity exercise on the intestinal polyp burden in ApcMin/+ mice.