Chronic clenbuterol treatment compromises force production without directly altering skeletal muscle contractile machinery

Abstract

Key pointsr Clenbuterol is an adrenergic receptor agonist known to induce skeletal muscle hypertrophy and a shift towards faster muscle fibres, when administered chronically at high doses.r However, when normalized to the muscle surface area, the increase in muscle force is no longer increased and even depressed.r We show that muscle contraction and relaxation force kinetics were significantly reduced particularly in fast contracting muscles.r We show that action potential-elicited Ca 2+ transients were depressed in the fast contracting muscle.r Our data show that chronic clenbuterol treatment reduces contractile efficiency, with altered contraction and relaxation kinetics, but without directly altering the contractile machinery. Lower Ca 2+ release during contraction could partially explain these deleterious effects.Abstract Clenbuterol is a β 2 -adrenergic receptor agonist known to induce skeletal muscle hypertrophy and a slow-to-fast phenotypic shift. The aim of the present study was to test the effects of chronic clenbuterol treatment on contractile efficiency and explore the underlying mechanisms, i.e. the muscle contractile machinery and calcium-handling ability. Forty-three 6-week-old male Wistar rats were randomly allocated to one of six groups that were treated with either subcutaneous equimolar doses of clenbuterol (4 mg kg −1 day −1 ) or saline solution for 9, 14 or 21 days. In addition to the muscle hypertrophy, although an 89% increase in absolute maximal tetanic force (P o ) was noted, specific maximal tetanic force (sPo) was unchanged or even depressed in the slow twitch muscle of the clenbuterol-treated rats (P < 0.05). The fit of muscle contraction and relaxation force kinetics indicated that clenbuterol treatment significantly reduced the rate constant of force development and the slow and fast rate constants of relaxation in extensor digitorum longus muscle (P < 0.05), and only the fast rate constant of relaxation in soleus muscle (P < 0.05). Myofibrillar ATPase activity increased in both relaxed and activated conditions in soleus (P < 0.001), suggesting that the depressed specific tension was not due to the myosin head alteration itself. Moreover, action potential-elicited Ca 2+ transients in flexor digitorum brevis fibres (fast twitch fibres) from clenbuterol-treated animals demonstrated decreased amplitude G. Py and C. Ramonatxo contributed equally to the study. after 14 days (−19%, P < 0.01) and 21 days (−25%, P < 0.01). In conclusion, we showed that chronic clenbuterol treatment reduces contractile efficiency, with altered contraction and relaxation kinetics, but without directly altering the contractile machinery. Lower Ca 2+ release during contraction could partially explain these deleterious effects.

Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

“…A recent study also supported the notion of the paradoxical less hypertrophic effect of CB on SOL, compared to the extensor digitorum longus muscle (Py et al. ). Since β ‐AR signaling represents a therapeutic target for the management of skeletal muscle wasting and weakness, it is important to understand the mechanisms underlying the differential hypertrophic effect of CB on fast‐ and slow‐twitch muscles (Kissel et al.…”

“…Although the physiological relevance of this difference is unclear, CB is paradoxically less effective in inducing hypertrophy of slow-twitch muscle, such as soleus muscle (SOL) (Ryall et al 2002), compared to fast-twitch muscles, such as tibialis anterior muscle (TA) (Shi et al 2007), extensor digitorum longus muscle (Ryall et al 2002;Shi et al 2007), and masseter muscle (Ohnuki et al 2014). A recent study also supported the notion of the paradoxical less hypertrophic effect of CB on SOL, compared to the extensor digitorum longus muscle (Py et al 2015). Since b-AR signaling represents a therapeutic target for the management of skeletal muscle wasting and weakness, it is important to understand the mechanisms underlying the differential hypertrophic effect of CB on fast-and slowtwitch muscles (Kissel et al 1998;Lynch and Ryall 2008).…”

Early structural and functional signature of 3‐day human skeletal muscle disuse using the dry immersion model

“…This was demonstrated in Py's study in 2015, in which a clear diminution in the Ca 2+ muscle transient of flexor digitorum brevis muscle (similar to the extensor digitorum longus phenotype) was associated with clenbuterol (beta 2 agonist) treatment (Py et al . ). This could contribute to the slower kinetics of muscle contraction and strongly suggests that dry immersion acts on some of the processes involved in excitation–contraction coupling, thereby modulating force and contractility characteristics, probably via an alteration in calcium handling.…”

Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic β2-adrenergic stimulation in men

“…␤ 2 -Adrenoceptors are abundant throughout the human body and are widely expressed in various tissues (44). Chronic administration of oral ␤ 2 -agonists has been shown to enhance muscle force and power output during maximal cycling in humans (10,12,39,40,45,69), which based on observations in animals, have been speculated to be attributed to hypertrophy or changes in fiber type composition of skeletal muscle (21,23,51,63,65,81). However, limited mechanistic insight exists in humans that can explain enhancements in muscle force and power output during maximal cycling.…”

“…While it is well described that chronic ␤ 2 -adrenergic stimulation induces muscle hypertrophy in animals (23,63,67), no such effect has been observed in healthy humans (10,39,40,45). This discrepancy may be related to methodology, since human studies relied on measurements of changes in body composition, whereas animal studies determined changes in the cross-sectional area (CSA) and specific weight of skeletal muscle (9,21,66,81).…”