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Abstract
The seemingly uniform striation pattern of skeletal muscles, quantified in terms of sarcomere lengths (SLs), is inherently non-uniform across all hierarchical levels. The SL non-uniformity theory has been used to explain the force creep in isometric contractions, force depression following shortening of activated muscle, and residual force enhancement following lengthening of activated muscle. Our understanding of sarcomere contraction dynamics has been derived primarily from in vitro experiments using regular bright-field light microscopy or laser diffraction techniques to measure striation/diffraction patterns in isolated muscle fibers or myofibrils. However, the collagenous extracellular matrices present around the muscle fibers, as well as the complex architecture in the whole muscles may lead to different contraction dynamics of sarcomeres than seen in the in vitro studies. Here, we used multi-photon excitation microscopy to visualize in situ individual sarcomeres in intact muscle tendon units (MTUs) of mouse tibialis anterior (TA), and quantified the temporal changes of SL distribution as a function of SLs in relaxed and maximally activated muscles for quasi-steady state, fixed-end isometric conditions. The corresponding muscle forces were simultaneously measured using a force transducer. We found that SL non-uniformity, quantified by the coefficient of variation (CV) of SLs, decreased at a rate of 1.9–3.1%/s in the activated muscles, but remained constant in the relaxed muscles. The force loss during the quasi-steady state likely did not play a role in the decrease of SL non-uniformity, as similar force losses were found in the activated and relaxed muscles, but the CV of SLs in the relaxed muscles underwent negligible change over time. We conclude that sarcomeres in the mid-belly of maximally contracting whole muscles constantly re-organize their lengths into a more uniform pattern over time. The molecular mechanisms accounting for SL non-uniformity appear to differ in active and passive muscles, and need further elucidation, as do the functional implications of the SL non-uniformity.
Highlights
The striation patterns of skeletal muscle carry important functional information, as they reflect the amount of overlap between the thick and thin filaments within a sarcomere, and the amount of steady-state, maximal, isometric force that a muscle can generate (Gordon et al, 1966)
Due to the technical difficulties associated with observing individual sarcomeres in a whole muscle, there is a lack of understanding of the dynamic behavior of sarcomeres residing in muscles, where thousands of muscle fibers are assembled by collagenous extracellular matrices in a complex architecture (Purslow, 1989, 2008; Heemskerk et al, 2005; Azizi et al, 2008; Lovering et al, 2013)
In G4, 60.6% of the total forces were contributed by the passive forces, while the remaining 39.4% came from the active forces (Figure 4A)
Summary
The striation patterns of skeletal muscle carry important functional information, as they reflect the amount of overlap between the thick and thin filaments within a sarcomere, and the amount of steady-state, maximal, isometric force that a muscle can generate (Gordon et al, 1966). As the muscle and its sarcomeres elongate over the descending limb of the force-length curve, the actomyosin-based active forces decrease (Gordon et al, 1966), whereas the passive forces caused by the extracellular matrices and intracellular titin increase (Gordon et al, 1966; ter Keurs et al, 1978; Leonard and Herzog, 2010; Wood et al, 2014) This shift in relative force contribution between passive structural and active contractile elements may potentially alter the sarcomere contraction dynamics, thereby affecting force production. In view of the apparent importance of SL non-uniformity on muscle properties, tracking the time history of SL distribution in whole muscles prior to and during muscle activation may provide new insight into the influence of extracellular matrices on sarcomere mechanics and inter-sarcomeric interactions
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