β₂‐Agonist administration reverses muscle wasting and improves muscle function in aged rats

Abstract

The beta2-adrenoceptor agonist (beta2-agonist) fenoterol has potent anabolic effects on rat skeletal muscle. We conducted an extensive dose-response study to determine the most efficacious dose of fenoterol for increasing skeletal muscle mass in adult rats and used this dose in testing the hypothesis that fenoterol may have therapeutic potential for ameliorating age-related muscle wasting and weakness. We used adult (16-month-old) rats that had completed their growth and development, and old (28-month-old) rats that exhibited characteristic muscle wasting and weakness, and treated them daily with either fenoterol (1.4 mg kg(-1), i.p), or saline vehicle, for 4 weeks. Following treatment, functional characteristics of fast-twitch extensor digitorum longus (EDL) and predominantly slow-twitch soleus muscles of the hindlimb were assessed in vitro. Untreated old rats exhibited a loss of skeletal muscle mass and a decrease in force-producing capacity, in both fast and slow muscles, compared with adult rats (P < 0.05). However, there was no age-associated decrease in skeletal muscle beta-adrenoceptor density, nor was the muscle response to chronic beta-agonist stimulation reduced with age. Thus, muscle mass and force-producing capacity of EDL and soleus muscles from old rats treated with fenoterol was equivalent to, or greater than, untreated adult rats. The increase in mass and strength was attributed to a non-selective increase in the cross-sectional area of all muscle fibre types, in both the EDL and soleus. Fenoterol treatment caused a small increase in fatiguability due to a decrease in oxidative metabolism in both EDL and soleus muscles, with some cardiac hypertrophy. Further studies are needed to fully separate the desirable effects on skeletal muscle and the undesirable effects on the heart. Nevertheless, our results demonstrate that fenoterol is a powerful anabolic agent that can restore muscle mass and strength in old rats, and provide preliminary evidence of therapeutic potential for age-related muscle wasting and weakness.

Myofibrillar myosin ATPase activity in hindlimb muscles from young and aged rats

“…However, there was no significant difference in MHC isoform expression between muscles from young and aged rats. Age-related shifts in MHC isoform have been reported in some studies of rodent muscles (Degens et al, 1998;Larsson et al, 1993;Li and Larsson, 1996) but not others (Gonzalez et al, 2003;Phillips et al, 1993;Ryall et al, 2004). These discrepancies are likely due to the various species, strains, muscles, ages, and techniques to quantitate MHC isoforms that were utilized in the studies.…”

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

“…While all three β‐adrenergic receptor types are present in skeletal muscle, there is a 10‐fold increased proportion of the β2 isoform in skeletal muscle (Santulli & Iaccarino, 2013). An age‐related decline in responsiveness to β2‐ARs has been proposed (Ford, Dachman, Blaschke & Hoffman, 1995), and β2 receptor agonists have reversed age‐related muscle weakness and wasting in rats (Ryall, Plant, Gregorevic, Sillence & Lynch, 2004). Because of the evidence supporting sympathetic innervation contributing to more youthful systemic physiology and NMJ morphology and function, we evaluated the presence of sympathetic innervation in our models via TH, β2‐AR, and NPY staining.…”

Parvalbumin Gene Transfer Impairs Skeletal Muscle Contractility in Old Mice

“…Dysregulation of skeletal muscle [Ca 2 + ] i has been implicated in the deleterious changes in muscle function with aging (Delbono et al, 1995;Wang et al, 2000;Gonzalez et al, 2003;Ryall et al, 2004;Schertzer et al, 2005;Weisleder et al, 2006;Russ et al, 2011). PV is a high-affinity, slow buffer of Ca 2 + , whose expression decreases in rat fasttwitch skeletal muscle with aging (by 63% in EDL muscles from 8-month-old rats compared with 24-month-old rats) (Cai et al, 2001).…”

“…One of the contributing factors is that the loss of muscle mass in aging is preceded by a slowing in the maximal rate of relaxation of the twitch and tetanus (Ryall et al, 2004;Schertzer et al, 2005;Russ et al, 2011) and a reduction in both peak tetanic intracellular Ca 2 + concentration ([Ca 2 + ] i ) and maximal tetanic force (Gonzalez et al, 2003;Ryall et al, 2004;Schertzer et al, 2005;Russ et al, 2011). The reduced peak tetanic [Ca 2 + ] i is attributed to an elevated resting [Ca 2 + ] i , which is 25% and 74% higher in soleus and extensor digitorum longus (EDL) muscles from old (27-30 months) compared with young rats (4-6 months), respectively (Fraysse et al, 2006).…”