Treatment Of Muscle Atrophy Research Articles

T.P.11 Effect of formoterol, a selective β2 adrenoceptor agonist, against nerve injury-induced muscle disuse atrophy

Skeletal muscle atrophy is common, debilitating and without acceptable treatment options. In humans, skeletal muscle atrophy occurs under various physiological and disease conditions, such as injury resulting in immobilization, critical illness, burns, cancer, COPD, liver disease, AIDS, congestive heart failure, diabetes. The reduction in strength and endurance associated with the involuntary loss of muscle mass results in functional limitations, loss of independence, reduced quality of life, increased disability, and increased mortality. Selective β2 adrenoceptor agonists, such as formoterol, elicit skeletal muscle hypertrophy, which is associated with increased force producing capacity in both fast- and slow-twitch muscles. Hypertrophy can be blocked by selective β2 adrenoceptor antagonist or genetic deletion of the β2 adrenoceptor. Several studies have shown potential efficacy of β2 adrenoceptor agonists in addressing muscle wasting in many animal species and humans. In this report, the effect of formoterol against a rodent model of muscle disuse atrophy was evaluated. The disuse atrophy was induced by cuff crushing-based nerve injury which is leading to neuropathic pain and eventually muscle disuse. It is known that selective β2 adrenoceptor agonists are effective against neuropathic pain, although the effect on muscle atrophy and function has not been evaluated yet. Therefore, formoterol was tested in this model in both prevention and therapeutic modes. The disuse atrophy was significantly prevented, and recovery from the atrophy was also significantly promoted by the formoterol treatment. In conclusion, formoterol is effective in the nerve injury-induced muscle disuse atrophy, and selective β2 adrenoceptor agonists might be a potential therapeutic option for treating muscle atrophy conditions caused by disuse and immobilization due to injury and critical illness.

476. Molecular Treatment of Muscle Atrophy Caused by Focal Nerve Injury

476. Molecular Treatment of Muscle Atrophy Caused by Focal Nerve Injury

Inhibition of Atrogin-1/MAFbx Expression by Adenovirus-Delivered Small Hairpin RNAs Attenuates Muscle Atrophy in Fasting Mice

Atrogin-1 or muscle atrophy F-box (MAFbx) is a major atrophy-related E3 ubiquitin ligase highly expressed in skeletal muscle during muscle atrophy and other disease states such as sepsis, cancer cachexia, and fasting. In this paper, we report experiments inhibiting MAFbx activity in fasting mice and in the skeletal myoblast cell line C2C12 via an adenovirus-mediated small hairpin RNA (shRNA) expression system in order to assess its suitability as a therapeutic target. Our results demonstrated that downregulation of MAFbx by shRNAs attenuated muscle loss induced by fasting in mice. Furthermore, we showed that when MAFbx expression was blocked both in cells and in fasting mice, the level of a myogenic factor, MyoD, was upregulated; whereas a muscle negative regulator, growth differentiation factor (GDF)-8 (myostatin), was suppressed. Our results also suggested that lower levels of MAFbx could also enhance muscle cell differentiation that corresponded to the reduced expression of GDF-8 and the increased level of MyoD. Taken together, the present study showed that MAFbx could be a potential molecular target for treating muscle atrophy.

Emerging Ideas: Matrix Metalloproteinase-2 in Muscle Atrophy

BackgroundMuscle atrophy impacts almost every patient seen for orthopaedic conditions. Unfortunately, no effective treatment is available to date. Matrix metalloproteinases (MMPs), especially MMP-2, are involved in skeletal muscle atrophy. MMP-2 null mice reportedly have substantially reduced muscle atrophy after tendon transection compared with wild-type mice, suggesting MMP-2 plays an important role in muscle atrophy. Although the exact mechanisms remain unknown, a newly-discovered intracellular form of MMP-2 suggests a possible novel mechanism of MMP-2 digesting muscle matrix during muscle atrophy. I propose a new pharmacologic treatment for muscle atrophy using selective MMP-2 inhibitors.Questions/HypothesisI hypothesize: (1) intracellular MMP-2 plays an important role during muscle atrophy by digesting intramuscular matrix; (2) AP-1 and NFAT signal transduction pathways are responsible for expression and activation of the intracellular MMP-2 during muscle atrophy; and (3) specific MMP-2 inhibitors can serve as a novel pharmacologic strategy in treating disuse-induced muscle atrophy.Method of StudyExpression and activity of extracellular and intracellular MMP-2 will be determined in a mouse tendon transection model. The role of AP-1 and NFAT signal transduction pathways in MMP-2 transcriptional regulation in muscle atrophy will be determined using chromatin-immunoprecipitation (ChIP) and small interfering RNA (siRNA). I also will test the feasibility of treating muscle atrophy using selective MMP-2 inhibitors.SignificanceUnderstanding the signaling transduction pathway of extracellular and intracellular MMP-2 expression during muscle atrophy may lead to novel treatments for muscle atrophy that preserve the normal physiologic function of MMP-2.

Glycogen Synthase Kinase 3β Suppresses Myogenic Differentiation through Negative Regulation of NFATc3

Skeletal muscle atrophy is a prominent and disabling feature in many chronic diseases. Prevention or reversal of muscle atrophy by stimulation of skeletal muscle growth could be an important therapeutic strategy. Glycogen synthase kinase 3beta (GSK-3beta) has been implicated in the negative regulation of skeletal muscle growth. Since myogenic differentiation is an essential part of muscle growth, we investigated if inhibition of GSK-3beta is sufficient to stimulate myogenic differentiation and whether this depended on regulation of the transcription factor nuclear factor of activated T-cells (NFAT). In both myogenically converted mouse embryonic fibroblasts and C2C12 myoblasts, deficiency of GSK-3beta protein (activity) resulted in enhanced myotube formation and muscle-specific gene expression during differentiation, which was reversed by reintroduction of wild type but not kinase-inactive (K85R) GSK-3beta. In addition, GSK-3beta inhibition restored myogenic differentiation following calcineurin blockade, which suggested the involvement of NFAT. GSK-3beta-deficient mouse embryonic fibroblasts or myoblasts displayed enhanced nuclear translocation of NFATc3 and elevated NFAT-sensitive promoter transactivation, which was reduced by reintroducing wild type, but not K85R GSK-3beta. Overexpression of NFATc3 increased muscle gene promoter transactivation, which was abolished by co-expression of wild type GSK-3beta. Finally, stimulation of muscle gene expression observed following GSK-3beta inhibition was strongly attenuated in NFATc3-deficient myoblasts, indicating that this response requires NFATc3. Collectively, our data demonstrate negative regulation of myogenic differentiation by GSK-3beta through a transcriptional mechanism that depends on NFATc3. Inhibition of GSK-3beta may be a potential strategy in prevention or treatment of muscle atrophy.

Undesirable effects of Cardiotrophin-1 (CT-1) on normal muscles as an agent treating denervation muscle atrophy

目的 探讨应用心脏营养素-1(cardiotrophin-1,CT-1)治疗失神经骨骼肌萎缩的有效剂量和安全剂量,观察不同剂量的CT-1对正常骨骼肌、心肌和血管平滑肌的副作用.方法 取Swiss小鼠80只,随机分成8组,每组分别于胫神经切断术后连续腹腔注射重组小鼠CT-1(rmCT-1)40、60、80、100、120、140、160μg·kg-1·d-1,剩余1组腹腔注射等体积CT-1溶媒,28d后称量失神经侧腓肠肌、正常侧腓肠肌和心脏的湿重;测量胸主动脉平滑肌厚度;检测正常腓肠肌中α-actin和MHC Ⅱa以及心肌中β-MHC的表达、胸主动脉血管平滑肌细胞中α-actin的含量.结果 采用腹腔注射给药,当CT-1用量达到60μg·kg-1·d-1时,开始对失神经骨骼肌产生营养作用,并呈剂量依赖性增强,当给药剂量超过100 μg·kg-1·d-1后,出现对正常骨骼肌、心肌和血管平滑肌的影响.给药剂量达到120μg·kg-1·d-1时,开始促进心肌β-MHCmRNA的表达,增加正常心脏的湿重.当给药剂量达到140μg·kg-1·d-1时,开始促进正常骨骼肌α-actin和MHC Ⅱ amRNA的表达,以及骨骼肌湿重的增加,同时提高了主动脉血管平滑肌α-actin的含量,增加了血管平滑肌的厚度.结论 腹腔注射CT-1防治失神经骨骼肌萎缩的有效剂量为60 μg·kg-1·d-1,最高安全剂量为100 μg·kg-1·d-1.当给药剂量达到120 μg·kg-1·d-1时,开始出现心肌肥厚,当给药剂量达到140 μg·kg-1·d-1时,可导致正常骨骼肌的肥大和血管平滑肌的增厚。

Neuromuscular Electrical Stimulation and Volitional Exercise for Individuals With Rheumatoid Arthritis: A Multiple-Patient Case Report

Muscle atrophy is common in patients with rheumatoid arthritis (RA). Although neuromuscular electrical stimulation (NMES) is a viable treatment for muscle atrophy, there is no evidence about the use of NMES in patients with RA. The purposes of this multiple-patient case report are: (1) to describe the use of NMES applied to the quadriceps femoris muscles in conjunction with an exercise program in patients with RA; (2) to report on patient tolerance and changes in lean muscle mass, quadriceps femoris muscle strength (force-producing capacity), and physical function; and (3) to explore how changes in muscle mass relate to changes in quadriceps femoris muscle strength, measures of physical function, and patient adherence. Seven patients with RA (median age=61 years, range=39-80 years) underwent 16 weeks of NMES and volitional exercises. Lean muscle mass and strength of the quadriceps femoris muscle and physical function were measured before and after treatment. One patient did not tolerate the NMES treatment, and 2 patients did not complete at least half of the proposed treatment. Patients who completed the NMES and volitional exercise program increased their lean muscle mass, muscle strength, and physical function. Because of the small sample, whether NMES combined with exercises is better than exercise alone or NMES alone could not be determined. However, the outcomes from this multiple-patient case report indicate that NMES is a viable treatment option to address muscle atrophy and weakness in patients with RA. Strategies to increase tolerance and adherence to NMES are warranted.

Insights into muscle atrophy and recovery pathway based on genetic models

Muscle atrophy is a pervasive problem that occurs with disuse, aging, and a myriad of disease conditions. The purposes of this review are to describe recent advances in studying muscle atrophy that have elucidated pathways involved at the molecular level; to compare different types of atrophy--primary (e.g. bed rest, immobilization) and secondary (when the atrophy is related to pathology as well as disuse, e.g. injury, sepsis etc.) and their multiple common features; to review progress in studying the recovery process and clinical status. Major advances have been made at the molecular level. There are two phenotypes for muscle atrophy--primary, which is mainly related to disuse (e.g. bed), and secondary, when the atrophy is related to pathology as well as disuse. It appears that the two forms have multiple elements in common. Studies on the recovery process reveal a very complex sequence of events that are not the simple reverse of the muscle loss process. In contrast to the progress at the molecular level, progress in treating muscle atrophy or accelerating recovery has been disappointing. Although nutritional supplementation and pharmacological agents continue to have the potential to minimize muscle atrophy, given its minimal risks, exercise sets a very high standard for treatment options when medically appropriate. Identification of pathways and control points offers the potential for new approaches.

Mergla K + channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway

Skeletal muscle atrophy results from an imbalance in protein degradation and protein synthesis and occurs in response to injury, various disease states, disuse, and normal aging. Current treatments for this debilitating condition are inadequate. More information about mechanisms involved in the onset and progression of muscle atrophy is necessary for development of more effective therapies. Here we show that expression of the mouse ether-a-go-go related gene (Merg1a) K+ channel is up-regulated in skeletal muscle of mice experiencing atrophy as a result of both malignant tumor expression and disuse. Further, ectopic expression of Merg1a in vivo induces atrophy in healthy wt-bearing mice, while expression of a dysfunctional Merg1a mutant suppresses atrophy in hindlimb-suspended mice. Treatment of hindlimb-suspended mice with astemizole, a known Merg1a channel blocker, inhibits atrophy in these animals. Importantly, in vivo expression of Merg1a in mouse skeletal muscle activates the ubiquitin proteasome pathway that is responsible for the majority of protein degradation that causes muscle atrophy, yet expression of a dysfunctional Merg1a mutant decreases levels of ubiquitin-proteasome proteolysis. Thus, expression of Merg1a likely initiates atrophy by activating ubiquitin-proteasome proteolysis. This gene and its product are potential targets for prevention and treatment of muscle atrophy.

Research Findings

Singapore Researchers Discover the Obesity Protein. Treatment for Muscle Atrophy with Myostatin Protein.

Effect of high-intensity running in rectus femoris muscle fiber in rats

The effect of a 12-week high-intensity intermittent exercise program on fiber type composition and the oxidative capacity of rectus femoris skeletal muscle from 20 male Wistar rats (Trained, n=10; Sedentary, n=10) was histochemically determined. The training exercise program was developed in a motorized treadmill. It consisted of four running bouts of 2 min duration at 48 m/min, alternated with recovery intervals of 4 min. Training increased relative cross-sectional area of oxidative fibers (I, IIA, IIX) and decreased the same parameter in type IIB non-oxidative fibers ( P<0.001). Our results suggest that this type of strength exercise program is enough to induce changes in muscle fiber composition. This opens a possibility to use this kind of exercise in preventing and treating muscle atrophy.

On the treatment of muscle atrophy with very high frequency impulses.

The sciatic nerves of 10 rabbits were severed on both sides and very high frequency impulses were administered to their gastrocnemius muscle groups unilaterally. In 3 to 62 days after the beginning of the stimu-ation, the muscles groups were cut out at the insertion of the tendons on both sides and weighed, for estimating the degree of muscle atrophy in comparison. The results obtained were as follows: 1. The weight of the gastrocnemius muscles on the treated side in comparison with that of the muscles on the other side was always larger and apparently showed that such a treatment was effective in controling muscle atrophy. 2. The impulse treatment should be begun in a short period after the cutting off of the nervous control and should be continued in daily administration more than two months.