Piperine activates the thick filament of resting rat skeletal muscle, enhancing dynamic contractility in a fiber-type-dependent manner
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Thick-filament activation, whereby myosin heads transition from an OFF to an ON state, is a key regulatory step in muscle contraction and a promising therapeutic target. The availability of ON-state myosin heads governs dynamic muscle contractility, which is critical to physical function and well-being. Thus, compounds that induce thick-filament activation in skeletal muscle are warranted to explore this therapeutic potential. Piperine, an alkaloid from black pepper, binds to myosin and increases isometric force at submaximal activation levels in both fast and slow-twitch skeletal muscle. The mechanism underlying this effect remains unclear, but may involve thick-filament activation, as shown in cardiac muscle. During contraction, myosin heads naturally shift from the OFF to the ON state, but the kinetics and extent of this transition are fiber-type dependent. Therefore, it remains to be clarified how piperine affects dynamic contractions in fast-and slow-twitch skeletal muscles. We addressed these gaps using fiber small-angle X-ray diffraction and intact-muscle ex vivo contractility experiments on rat extensor digitorum longus (fast-twitch) and soleus (slow-twitch) muscles. X-ray diffraction data suggest that piperine promotes an OFF-to-ON transition of myosin in resting skeletal muscle, increasing the pool of myosin heads available for force generation. Functionally, piperine-induced thick-filament activation substantially enhanced dynamic contractility in both muscle types, with greater improvements in slow-twitch versus fast-twitch muscle under conditions of maximal activation. These findings establish piperine as a tool to probe thick-filament activation in skeletal muscle and guide future studies toward fiber-type–specific effects on recruitment of the contractile reserve capacity.
Significance Statement
Targeting myosin, a key motor protein in muscle, to restore muscle function has become a major focus in muscle physiology. Yet no approved therapies exist for skeletal muscle, making the identification of compounds with myosin-activating properties a research priority. Skeletal muscles come in two main types: slow (postural) and fast (powerful). Here, we investigated piperine, a natural compound from black pepper, and found that it activates myosin in resting skeletal muscles, making muscles more readily activated. These molecular effects translated into substantial muscle-type-dependent increases in the muscles’ ability to recruit their contractile reserve capacity during complex contractions. Our findings propose piperine as a tool for investigating fundamental questions of muscle contraction and the therapeutic opportunities of myosin-activation in skeletal muscle.
