Massive sarcomerogenesis in human skeletal muscle following long-term eccentric exercise intervention

Sarcomerogenesis, the addition of serial sarcomeres in skeletal muscle myofibrils and fibres, is a natural occurrence during growth and maturation of animals, including humans. However, the detailed mechanisms that allow for sarcomerogenesis are not fully understood. In some diseases, such as cerebral palsy in children, sarcomerogenesis appears to be inhibited or at least reduced,^1,2 often causing severe restrictions in muscle and joint function.

Eccentric exercise has been considered a potential trigger for sarcomerogenesis, but results in the literature are contradictory.3, 4, 5 In cases where sarcomerogenesis was observed, the increase in serial sarcomere number tended to be small and of questionable functional relevance.⁶ Exploring sarcomerogenesis in humans exposed to excentric exercise has been limited due to the difficulty of measuring serial sarcomere numbers. However, with the advancement of micro-endoscopic techniques combined with second harmonic generation microscopy, visualizing individual sarcomeres in life humans⁷ and animals^7,8 has become possible. Pincheira et al.⁹ were the first to quantify fascicle length, average sarcomere length, and serial sarcomere number following eccentric exercise training in humans. Specifically, they made these measurements in the long head of the biceps femoris muscle following 3 weeks of Nordic hamstring exercise, an exercise specifically designed to eccentrically load the human hamstring muscles, including the long head of the biceps femoris.¹⁰ They found a 21% increase in fascicle length and a 17% increase in sarcomere length in the distal portion of the biceps femoris, while the number of sarcomeres in series did not change significantly. In an editorial,¹¹ it was suggested, based on previous findings on animal models, that maybe the 3-week intervention period might have been too short for effective sarcomerogenesis, and that the sarcomere elongations paralleling the fascicle elongations were a necessary precursor to sarcomerogenesis.

In the current edition of the Journal of Sport and Health Science, the same group of researchers extended the eccentric Nordic hamstring intervention period to 9 weeks.¹² In agreement with the results from their 3-week intervention protocol, they found that fascicle length also increased with the 9-week protocol. However, in contrast to the 3-week protocol, the extended protocol resulted in an increase in serial sarcomere number. Combined, the results from their studies suggest the following temporal sequence: The Nordic eccentric exercise, as performed in their intervention protocol, results in an increase in fascicle length that is initially accounted for by increases in sarcomere length but later, at 9 weeks, is fully accounted for by an increase in the serial number of sarcomeres. These time-dependent increases in muscle/fascicle length agree with previous observations regarding muscle growth induced by passive stretch in chicken wing muscles.¹³

An interesting side issue is that fascicle lengths measured in the distal and central regions of the long head of the biceps femoris increased from 21% and a non-significant tendency at 3 weeks, to 33% and 19%, respectively at 9 weeks, suggesting fascicle length adaptations were not fully completed in the 3-week intervention period.^9,12

However, by far the most important, and simultaneously surprising result, was the increase in serial sarcomere number in the distal (49% increase) and central (25% increase) regions of the long head of the biceps femoris following the 9-week intervention period.¹² To our knowledge, these are the greatest reported increases in serial sarcomere number associated with any eccentric training intervention protocol. Also, since the fascicle length increases were smaller (33% distal and 19% central region) than the corresponding increases in serial sarcomere number (49% distal and 25% central region), it must be assumed that the average sarcomere length was decreased after the 9-week intervention period, but sarcomere shortening did not reach statistical significance. This result may be associated with the relatively low number of independent observations or the fact that some of the results obtained before and after the intervention period were from different participants, and thus not all comparisons were matched. However, when analyzing just the matched pairs before and after intervention, the increases in serial sarcomere number remained similar to those reported in the original manuscript (44%, n = 5 matched pairs, vs. 49% reported for the distal region, and 26% n = 9 matched pairs, vs. 25% reported for the central region). Noteworthy, each of the 14 matched pair comparisons showed an increase in serial sarcomere number following the 9-week Nordic hamstring exercise intervention, but the individual increases differed greatly across subjects ranging from 9% to 58%.

One would assume that the average increase in serial sarcomere number of 25%–49%, as reported in their study,¹² would be associated with corresponding changes in the mechanical properties of the muscle. For example, one would expect peak isometric force (the plateau of the force–length relationship) to occur at longer muscle length, and the speed of unloaded shortening (maximal contraction speed of the force–velocity relationship) to be increased proportionally with the increase in relative serial sarcomere number. However, neither changes in force–length nor force–velocity properties of the hamstring muscles were measured from before to after the Nordic hamstring exercise intervention, thus preventing interpretation of the potential functional significance of the observed increases in serial sarcomere number.

No measurements of sarcomere length in the activated muscle were made by Andrews et al.¹² as the authors mentioned that this was presently not feasible in humans, although active, dynamic sarcomere length measurements using their approach have been made in live animals.^7,14 Even in the absence of direct sarcomere length measurements in the active muscle, fascicle length measurements using ultrasound imaging during dynamic muscle contractions have been made for decades,^15,16 and knowing the instantaneous fascicle length and the (constant) number of serial sarcomeres, mean sarcomere length could have been determined readily for the Nordic hamstring exercise. Knowing the interindividual variability in muscle fascicle/sarcomere elongation in the eccentric action of the active part of the Nordic hamstring exercise in the current report may have provided additional information on the mechanisms underlying the observed sarcomerogenesis and insights into the large interindividual differences in muscle adaption reported in their study.

It is well known that fascicle and muscle length changes do not necessarily occur in parallel,17, 18, 19 and that eccentric muscle action can be associated with purely concentric or isometric action of the fascicles/sarcomeres.²⁰ Hamstring muscle forces would be expected to increase while the Nordic exercise is progressing due to the increasing knee flexor moment required to perform the exercise in a controlled manner. Increasing force is associated with decreasing fascicle lengths which may, completely or to a certain extent, offset the expected fascicle elongations due to the elongation of the muscle tendon unit during the exercise.

Raiteri and colleagues²¹ reported that in the initial phase of the Nordic hamstring exercise, fascicles shorten while the muscle tendon unit is stretched, but in the latter phases of the exercise, fascicles lengthen by 2.5–6.0 mm for an average increase in muscle tendon unit length of about 10 mm. Since the initial shortening of the fascicles was not quantified, it is not known if the Nordic hamstring exercise resulted in a net elongation of fascicles from the onset of the exercise to peak force occurrence. In a study preceding their current report on in vivo sarcomerogenesis in the long head of the biceps femoris, Pincheira et al.²² also measured muscle tendon unit and fascicle elongations during the Nordic hamstring exercise. Like others,²¹ they too found that fascicle lengths in the first part (0%–80%) of the Nordic hamstring exercise remained nearly isometric, or even shortened slightly, while the muscle tendon unit lengthened. They observed fascicle elongations only in the last 20% of the exercise, when the corresponding electromyographical activity decreased abruptly, as is typically observed when subjects cannot control the Nordic hamstring exercise and “collapse”. The question now arises, is the sarcomerogenesis observed in the current study¹² caused in the fascicle isometric/shortening phase (first 80% of the Nordic hamstring exercise), or in the last 20%, when a decrease in activation, and presumably a stark reduction in force, allows fascicles to elongate? Detailed individual analysis of fascicle elongation during the Nordic hamstring exercise, caused by differences in tendon stiffness, muscle strength, or competence in performing the exercise, might have provided insight as to the causes of the great interindividual variability in sarcomerogenesis.

Andrews and colleagues¹² used state of the art techniques to quantify increases in serial sarcomere numbers following an eccentric exercise training protocol. Not only is this the first clear indication of human skeletal muscle sarcomerogenesis following eccentric training, the average increase in serial sarcomere number (49% on average in the distal portion of the long head of the biceps femoris) is unprecedented and should provide motivation for exploring the limits of sarcomerogenesis, the molecular mechanisms underlying sarcomerogenesis and the corresponding implications for muscle properties and animal/human function.

Authors’ contributions

HdBF and WH conceived and discussed the idea for the commentary and drafted and edited the manuscript together. Both authors contributed equally to the manuscript, have read and approved the final version of the manuscript, and agree with the order of presentations of the authors.

Competing interests

Both authors declare that they have no competing interests.