Mammalian skeletal muscle is an extremely heterogeneous tissue, composed of a large variety of fiber types. These fibers, however, are not fixed units but represent highly versatile entities capable of responding to altered functional demands and a variety of signals by changing their phenotypic profiles. This adaptive responsiveness is the basis of fiber type transitions. The fiber population of a given muscle is in a dynamic state, constantly adjusting to the current conditions. The full range of adaptive ability spans fast to slow characteristics. However, it is now clear that fiber type transitions do not proceed in immediate jumps from one extreme to the other, but occur in a graded and orderly sequential manner. At the molecular level, the best examples of these stepwise transitions are myofibrillar protein isoform exchanges. For the myosin heavy chain, this entails a sequence going from the fastest (MHCIIb) to the slowest (MHCI) isoform, and vice-versa. Depending on the basal protein isoform profile and hence the position within the fast-slow spectrum, the adaptive ranges of different fibers vary. A simple transition scheme has emerged from the multitude of data collected on fiber type conversions under a variety of conditions.

Mammalian skeletal muscle fiber type transitions

The beta-adrenergic receptors (beta-AR) are present on the surface of almost every type of mammalian cell. These receptors are stimulated physiologically by the neurotransmitter, norepinephrine and the adrenal medullary hormone, epinephrine. There are three subtypes of beta-AR, namely, beta1-AR, beta2-AR, and beta3-AR; the pharmacological and physiological responses of an individual cell result from the particular mixture of the three beta-AR subtypes present on that cell. Species-specific structure (amino acid sequence) also causes modification of the function of a given beta-AR subtype. Knowledge of the beta-AR subtypes present in various cell types, coupled with knowledge of receptor structure (sequence), will allow an understanding of the complexity of physiological function regulated by beta-AR. Oral administration of some beta-AR agonists increases muscle and decreases fat accretion in cattle, pigs, poultry, and sheep. The large number of physiological functions controlled by beta-AR suggests that the mechanism(s) for the observed changes in carcass composition may be extremely complex. Any proposed mechanism must begin with the possibility of direct effects of the agonist on skeletal muscle and adipocyte beta-AR. However, many other mechanisms, such as modification of blood flow, release of hormones, or central nervous system control of feed intake may contribute to the overall effects observed with a given beta-AR agonist in a given species. Furthermore, the pharmacodynamic properties of a particular agonist are complex and expected to vary among species as well as within the same species at different ages or when fed different diets.

Overview of the effects of beta-adrenergic receptor agonists on animal growth including mechanisms of action

Control of fresh meat quality through manipulation of muscle fiber characteristics

had asthma or exercise induced bronchoconstriction.' The figures agreed with those of Weiler et al, who found self reported asthma in 12% of football players; basketball players had a low asthma prevalence.29 In a study from Portugal Gomes et al found normal bronchial responsiveness in elite runners.?0 In another study swimmers had a higher prevalence of asthma and bronchial hyperresponsiveness than other athletes and the authors postulated a relation with ambient swimming pool conditions.3' To our knowledge there are no other studies of skiers or other athletes performing exercise at low temperatures. From the few reports available there is no evidence that strenuous training by itself increases the risk of asthma. Strenuous training at low temperatures, however, seems to be pathogenetic for asthma, possibly due to the repeated breathing of large amounts of cold air.

https://www.bmj.com/content/bmj/307/6915/1329.full.pdf

Importance of placement of intra-articular steroid injections.

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.

Role of β-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease

The objectives of this study were 1) to determine how cellular growth of skeletal muscle is altered by the repartitioning agent cimaterol and 2) to determine if cimaterol alters endocrine status in association with its repartitioning effects. Thirty Dorset wether lambs were randomly assigned to a pre-treatment baseline group or received 0 or 10 ppm cimaterol in a complete, mixed, high-concentrate diet for 7 or 12 wk. Weights of biceps femoris (BF), semimembranosus (SM) and semitendinosus (ST) muscles were 32.8, 27.1 and 31.5% greater, respectively, in treated lambs at 7 wk, and were 22 to 24% greater at 12 wk. Longissimus (LD) cross-sectional area was 26 and 32% greater at these treatment intervals. Percent type I fibers declined significantly over the course of the experiment in ST, SM and LD, and cimaterol caused a small but significant reduction in percent type I fibers in the ST at 7 and 12 wk. Muscles from lambs fed cimaterol contained 50 and 75% more fibers that exhibited negative staining for phosphorylase activity. Mean cross-sectional area of type I and type II fibers in the combined portions of the ST were 30.4 and 29.3% greater, respectively, in cimaterol-fed lambs after 12 wk, while type I and type II fiber areas in the longissimus were only 13 and 15% greater, respectively. Cimaterol-induced hypertrophy of the ST resulted in both protein and RNA content being 30 to 35% greater (P<.01) at 7 and 12 wk, while DNA concentration was 22% less (P<.O1) at 7 wk. DNA concentration returned to normal by 12 wk. These results indicate that cimaterol elicits a rapid increase in muscle RNA and protein accretion without concurrent incorporation of satellite cell nuclei. Plasma insulin and insulin-like growth factor-1 (IGF-1) concentrations were 55 and 34% lower, respectively, in cimaterol-fed lambs. Plasma somatotropin concentration and area under the curve were 2.3 times greater (P<.01) in lambs fed cimaterol for 6 wk, while plasma cortisol, prolactin and glucose concentration were unaffected at 6 or 12 wk. The significant changes in endocrine status may be important in the mechanism(s) of cimaterol in altering muscle accretion.

Cimaterol-induced muscle hypertrophy and altered endocrine status in lambs.

Two experiments were conducted in which cimateroI [CL263,780; (anthranilo-nitrile, 5-[1hydroxy-2-(isopropylamino) ethyl]-)] was fed at 0 or 10 ppm in a complete, mixed, high-concentrate diet to assess effects on growth performance and repartitioning of tissue growth in young, rapidly growing lambs. Average daily gain and feed efficiency (F/G) were not altered in Dorset wether lambs fed cimaterol for 6 or 11 wk in Exp. 1. Average daily gain and F/G were improved 16% (P<.05) in Suffolk X Dorset ram lambs fed cimaterol for 5 wk, but not 10 wk in Exp. 2. Cimaterol increased dressing percent by at least 3 percentage units (P<.05), increased longissimus area 26 and 32% (P<.001), reduced 12th-rib fat thickness 66 and 32% (P<.001) and reduced kidney and pelvic fat 34 and 44% (P<.001) at 6 wk and 12 wk, respectively (Exp. 1). Proximal hindleg muscles were 26% heavier (P<.001) in cimaterol-fed lambs in Exp. 1. Fishmeal (FM) replaced an equal amount of soy protein (3% of diet) to create a 2 • 2 • 2 factorial arrangement in Exp. 2. Cimaterol effects on carcass traits and muscle growth were similar to those observed in Exp. 1. However, hindleg and foreleg muscle weights and longissmus area were 16% greater (P<.001) in FM-fed lambs at 10 wk, and the cimaterol-induced muscle hypertrophy was slightly reduced in these lambs. Fat measures were unaffected by FM. These data demonstrate that cimaterol effectively repartitions skeletal muscle and adipose tissue accretion, and fishmeal fed for 10 wk significantly enhances skeletal muscle growth in lambs. (

Effects of Cimaterol and Fishmeal on Performance, Carcass Characteristics and Skeletal Muscle Growth in Lambs

The objectives of this study were 1) to compare intermittent subcutaneous administration of human growth hormone-releasing factor (hGRF) at two doses with a similar regimen of ovine somatotropin (oST) for effects on growth and composition of gain in growing lambs and 2) to determine whether increasing the dietary amino acid availability enhances response to oST or hGRF. Eighty crossbred ewe and wether lambs (25.5 kg live weight) were assigned randomly in pairs to receive four daily injections of excipient, 40 micrograms oST/kg BW, 5 micrograms hGRF/kg BW or 10 micrograms hGRF/kg BW for 42 (n = 80) or 56 (n = 40) d. Doses were adjusted weekly for BW. Mean plasma oST concentrations increased from 2.03 ng/ml prior to treatment to 20.64, 4.80 and 5.45 ng/ml with oST, 5 and 10 micrograms/kg hGRF doses, respectively. Lambs did not become refractory to hGRF. Cumulative gain increased approximately 18% with 7 wk of treatment with oST and the low dose of hGRF (both P less than .01), and feed efficiency improved 21% with oST and 18% with both doses of hGRF (both P less than .05). Carcass lipid accretion rate decreased 22% to 30% (P less than .001), and carcass protein accretion rate increased 30% to 36% (P less than .001) with hGRF and oST treatment, respectively. Addition of fishmeal to the diet at 4% to replace an equal amount of soy protein improved gain 8.5%; it improved efficiency 14.2% (P less than .05) across all treatments, and it significantly enhanced the effects of oST on feed efficiency (interaction P less than .12) and hind leg muscle weights.

V. K. Fishell

Papers

Cimaterol-induced muscle hypertrophy and altered endocrine status in lambs.

Effects of Cimaterol and Fishmeal on Performance, Carcass Characteristics and Skeletal Muscle Growth in Lambs

Exogenous human growth hormone-releasing factor and ovine somatotropin improve growth performance and composition of gain in lambs