After suffering a stroke, patients often are unable to use the arm on their affected side. Sometimes, they end up holding it close to their body, with the elbow flexed.
In a new study, Northwestern University and Shirley Ryan AbilityLab researchers have discovered that, in an attempt to adapt to this impairment, muscles actually lose sarcomeres – their smallest, most basic building blocks.
Stacked end to end (in series) and side to side (in parallel), sarcomeres make up the length and width of muscle fibers. By imaging biceps muscles with three noninvasive methods, the researchers found that stroke patients had fewer sarcomeres along the length of the muscle fiber, resulting in a shorter overall muscle structure.
The research was published today (June 25) in the Proceedings of the National Academy of Arts and Sciences.
This finding is consistent with the common patient experience of abnormally tight, stiff muscles that resist stretching, and it suggests that changes in the muscle potentially amplify existing issues caused by stroke, which is a brain injury. The team hopes this discovery can help improve rehabilitation techniques to rebuild sarcomeres, ultimately helping to ease muscle tightening and shortening.
“This is the most direct evidence yet that chronic impairments, which place a muscle in a shortened position, are associated with the loss of serial sarcomeres in humans,” said Wendy Murray, the study’s senior author.
“Understanding how muscles adapt following impairments is critical to designing more effective clinical interventions to mitigate such adaptations and to improve function following motor impairments.”
Murray is a professor of biomedical engineering at Northwestern’s McCormick School of Engineering, a professor of physical medicine and rehabilitation at the Northwestern University Feinberg School of Medicine and research scientist at the Shirley Ryan AbilityLab.
The research was completed in collaboration with Julius Dewald, professor of physical therapy and human movement sciences and of physical medicine and rehabilitation at Feinberg, professor of biomedical engineering at McCormick, and research scientist at Shirley Ryan AbilityLab.
First demonstration in humans
Measuring just 1.5 to 4.0 microns in length, sarcomeres comprise two main proteins: actin and myosin. When these proteins work together, they enable a muscle to contract and produce force. Although previous animal studies have found that muscles lose serial sarcomeres after a limb is immobilized in a cast, the phenomenon had never before been demonstrated in humans. In the animal studies, muscles that were shorter because they lost serial sarcomeres also became stiffer.
“There is a classic relationship between force and length,” said Amy Adkins, a Ph.D. student in Murray’s laboratory and the study’s first author. “Given that the whole muscle is composed of these building blocks, losing some of them affects how much force the muscle can generate.”
To conduct the study in humans, the researchers combined three non-invasive medical imaging techniques: MRI to measure muscle volume, ultrasound to measure bundles of muscle fibers and two-photon microendoscopy to measure the microscopic sarcomeres.
Imaging opens new possibilities
Combining these technologies at Northwestern and Shirley Ryan AbilityLab, the researchers imaged biceps from seven stroke patients and four healthy participants. Because stroke patients are more affected on one side of their body, the researchers compared imaging from the patients’ affected side to their unaffected side as well as to images from the healthy participants.
The researchers found that the stroke patients’ affected biceps had less volume, shorter muscle fibers and comparable sarcomere lengths. After combining data across scales, they found that affected biceps had fewer sarcomeres in series compared to the unaffected biceps. The differences between stroke patients’ arms were greater than in in healthy participants’ arms, indicating that the differences were associated with stroke.
By combining medical imaging to better view muscle structure, the study also establishes that it is possible to study muscle adaptations in sarcomere number in humans. Before two-photon microendoscopy, human studies were limited either to examining dissected tissues in anatomy labs, which give imperfect insight into how muscles adapt to injury and impairment, measuring sarcomere lengths during surgery or from a muscle biopsy, which restricts who can participate in the study.
“In almost every facet of our world, there is an important relationship between how something is put together (its structure) and how it works (its function),” the researchers said. “Part of the reason medical imaging is such a valuable resource and clinical tool is that this is also true for the human body, and imaging gives us an opportunity to measure structure.”
Alteration in muscle properties due to motor dysfunction negatively impacts stroke survivors’ mobility and self-care and thus has been a major clinical concern when treating stroke patients. Patients post-stroke often show substantial changes in muscle tone/tension, including the initial flaccid phase (i.e., reduced muscle tension) starting shortly after a stroke and the subsequent development of muscle spasticity that increases muscle tension in the affected limbs (Dietz and Berger, 1983; Hufschmidt and Mauritz, 1985; Lee et al., 1987; Feit et al., 1989; Sinkjaer et al., 1993, 1996; Sinkjaer and Magnussen, 1994; Booth et al., 2001).
Although altered muscle tension following stroke, such as spasticity, has been associated with changes in the muscle fiber and sarcomere properties (Lieber and Friden, 2002), the role of the altered muscle tension following stroke in sarcomeric adaptation remains unclear. Changes of passive muscle properties after stroke have been studied at the joint level (Chung et al., 2004, 2008), and ultrasound studies have demonstrated the muscle contractility and tendon characteristics post-stroke (Gao and Zhang, 2008; Zhao et al., 2008).
Aforementioned research investigated muscle functions from a system level at a particular time (i.e., a cross-sectional study design); a better understanding through in vivo investigations of the changes in sarcomere morphology and muscle tension at several consequential time points may help advance clinical guidance (Smeulders and Kreulen, 2006).
Muscle cell adaptation (sarcomerogenesis) has been thought to be a process responsible for the maintenance of the optimal length and force-length relationship by adjusting the number of sarcomeres in series, so that the muscle could be used efficiently (Herring et al., 1984).
The process of muscle cell adaptation is activated in response to the demand of workload as observed in previous studies involving immobilization and lengthening (Goldspink et al., 1974; Williams and Goldspink, 1978; Williams et al., 1999; Gajdosik, 2001; Caiozzo et al., 2002; Lindsey et al., 2002; Coutinho et al., 2004), hind-limb unloading (Kasper and Xun, 2000; Wang et al., 2006), and tenotomy (Baker and Hall-Craggs, 1978). However, little is known regarding changes in the intrinsic properties of muscle cells following stroke.
It has been suggested that an intact innervation, both descending and ascending pathways, is critical for proper adjustment/adaptation of sarcomere length, and sarcomerogenesis might occur at a slower rate if innervation is compromised (McLachlan and Chua, 1983; Huijing and Jaspers, 2005; Swaroop et al., 2009).
For example, in a rat leg lengthening study with the groups of lengthening only, lengthening with Botox, lengthening with neurectomy, and sham surgery, the number of serial sarcomeres in the soleus muscle fibers of the lengthening only group had a significantly more addition of sarcomeres in series when compared to the other three groups (Swaroop et al., 2009).
In children with cerebral palsy (CP), impaired sarcomeric adaptation to the stretching of the muscle during growth/development has been thought to be the cause of the observed increased sarcomere length in this neurological patient population (Dayanidhi and Lieber, 2014; Matthiasdottir et al., 2014; Mathewson and Lieber, 2015; Kinney et al., 2017). In ischemic stroke, however, it remains poorly understood whether and how the muscle cells can adapt in response to changes in muscle mechanical environment throughout pathology progression.
Quantitative investigations to evaluate muscle fiber tension in vivo and its influence on sarcomeric adaptation post-stroke are limited because of the difficulties in human subject testing. Pre-clinical rodent models allow researchers to study neurological disease and motor system dysfunction (Farr and Whishaw, 2002; Farr et al., 2006; Granziera et al., 2007). Mice with induced stroke demonstrated similar functional and motor deficits to what have been observed in stroke patients, such as locomotor activity, gait, and limb tone (Hunter et al., 2000; Li et al., 2004).
Thus, the objective of this study was to investigate the sarcomeric adaptation and the changes in muscle tension following stroke using a mouse ischemic stroke model. We hypothesized that changes in muscle tension due to a neural injury would not lead to sarcomeric adaptation due to impaired innervation in mice following ischemic stroke.
reference link : https://www.frontiersin.org/articles/10.3389/fphys.2020.581846/full
More information: Amy N. Adkins et al, Serial sarcomere number is substantially decreased within the paretic biceps brachii in individuals with chronic hemiparetic stroke, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2008597118