Chronic treatment with the beta(2)-adrenoceptor agonist prodrug BRL-47672 impairs rat skeletal muscle function by inducing a comprehensive shift to a faster muscle phenotype.
ABSTRACT Discovering approaches to maintain or improve muscle function (fatigue resistance) in patients with cachexia, postoperative weakness, and sarcopenia is of clinical importance. beta(2)-Agonist treatment increases muscle mass, yet it alters fiber proportions such that the net consequences on muscle function remain unclear. In the present study, we focus on the contractile and metabolic consequences of chronic treatment with the beta(2)-agonist prodrug BRL-47672 (BRL). Gastrocnemius-plantaris-soleus (GPS) muscles were harvested at rest and studied for fatigue characteristics during 4 and 20 s of isometric stimulation (30 Hz; 10 V; 200 ms) using the perfused hind limb model. BRL treatment increased GPS mass by 21% (P < 0.05), whereas greater fatigue occurred during 20 s of contraction (45% less work; P < 0.05). Phenotypically, BRL resulted in 17% more type IIb myosin heavy chain protein expression (P < 0.001) and greater adenine nucleotide catabolism during 20 s of contraction (P < 0.05). Chronic BRL treatment impaired maximal lipid oxidation capacity by 30% (P < 0.05) and reduced glutamate dehydrogenase activity by 15% (P < 0.05). We conclude that beta(2)-agonist induced muscle hypertrophy may be clinically limited as impaired energy metabolism and function occur, presumably as a consequence of the shift in muscle phenotype.
Article: Role of beta-adrenoceptor signaling in skeletal muscle: implications for muscle wasting and disease.[show abstract] [hide abstract]
ABSTRACT: The importance of beta-adrenergic signaling in the heart has been well documented, but it is only more recently that we have begun to understand the importance of this signaling pathway in skeletal muscle. There is considerable evidence regarding the stimulation of the beta-adrenergic system with beta-adrenoceptor agonists (beta-agonists). Although traditionally used for treating bronchospasm, it became apparent that some beta-agonists could increase skeletal muscle mass and decrease body fat. These so-called "repartitioning effects" proved desirable for the livestock industry trying to improve feed efficiency and meat quality. Studying beta-agonist effects on skeletal muscle has identified potential therapeutic applications for muscle wasting conditions such as sarcopenia, cancer cachexia, denervation, and neuromuscular diseases, aiming to attenuate (or potentially reverse) the muscle wasting and associated muscle weakness, and to enhance muscle growth and repair after injury. Some undesirable cardiovascular side effects of beta-agonists have so far limited their therapeutic potential. This review describes the physiological significance of beta-adrenergic signaling in skeletal muscle and examines the effects of beta-agonists on skeletal muscle structure and function. In addition, we examine the proposed beneficial effects of beta-agonist administration on skeletal muscle along with some of the less desirable cardiovascular effects. Understanding beta-adrenergic signaling in skeletal muscle is important for identifying new therapeutic targets and identifying novel approaches to attenuate the muscle wasting concomitant with many diseases.Physiological Reviews 05/2008; 88(2):729-67. · 26.87 Impact Factor
Article: Antioxidant treatment of hindlimb-unloaded mouse counteracts fiber type transition but not atrophy of disused muscles.[show abstract] [hide abstract]
ABSTRACT: Oxidative stress was proposed as a trigger of muscle impairment in various muscle diseases. The hindlimb-unloaded (HU) rodent is a model of disuse inducing atrophy and slow-to-fast transition of postural muscles. Here, mice unloaded for 14 days were chronically treated with the selective antioxidant trolox. After HU, atrophy was more pronounced in the slow-twitch soleus muscle (Sol) than in the fast-twitch gastrocnemius and tibialis anterior muscles, and was absent in extensor digitorum longus muscle. In accord with the phenotype transition, HU Sol showed a reduced expression of myosin heavy chain type 2A (MHC-2A) and increase in MHC-2X and MHC-2B isoforms. In parallel, HU Sol displayed an increased sarcolemma chloride conductance related to an increased expression of ClC-1 channels, changes in excitability parameters, a positive shift of the mechanical threshold, and a decrease of the resting cytosolic calcium concentration. Moreover, the level of lipoperoxidation increased proportionally to the degree of atrophy of each muscle type. As expected, trolox treatment fully prevented oxidative stress in HU mice. Atrophy was not prevented but the drug significantly attenuated Sol phenotypic transition and excitability changes. Trolox treatment had no effect on control mice. These results suggest possible benefits of antioxidants in protecting muscle against disuse.Pharmacological Research 06/2010; 61(6):553-63. · 4.44 Impact Factor