Mathematical modeling of the dynamic mechanical behavior of neighboring sarcomeres in actin stress fibers

pre-printActin stress fibers (SFs) in live cells consist of series of dynamic individual sarcomeric units. Within a group of consecutive SF sarcomeres, individual sarcomeres can spontaneously shorten or lengthen without changing the overall length of this group, but the underlying mechanism is unclear. We used a computational model to test our hypothesis that this dynamic behavior is inherent to the heterogeneous mechanical properties of the sarcomeres and the cytoplasmic viscosity. Each sarcomere was modeled as a discrete element consisting of an elastic spring, a viscous dashpot and an active contractile unit all connected in parallel, and experiences forces as a result of actin filament elastic stiffness, myosin II contractility, internal viscoelasticity, or cytoplasmic drag. When all four types of forces are considered, the simulated dynamic behavior closely resembles the experimental observations, which include a low-frequency fluctuation in individual sarcomere length and compensatory lengthening and shortening of adjacent sarcomeres. Our results suggest that heterogeneous stiffness and viscoelasticity of actin fibers, heterogeneous myosin II contractility, and the cytoplasmic drag are sufficient to cause spontaneous fluctuations in SF sarcomere length. Our results shed new light to the dynamic behavior of SF and help design experiments to further our understanding of SF dynamics

Doctor of Philosophy

dissertationCells encounter mechanical cues from the environment to which they sense and respond. The actin cytoskeleton is the main network that can not only sense mechanical changes, but can also reorganize in response. Actin stress fibers are predominant in cultured fibroblast cells and are load-bearing structures of the cell. Here, in collaboration with others, I have investigated the mechanisms of stress fiber strain response and remodeling using fluorescently-labeled cytoskeletal proteins and live cell microscopy, traction force microscopy, and genetic manipulation to assess these mechanisms. High resolution image acquisition and analysis have provided novel insight into the mechanosensitivity of actin stress fibers. Specifically, the actin-associated protein zyxin has been implicated in an actin repair mechanism with mechanical consequences. We discovered a novel zyxin-mediated actin repair mechanism that restored structural and mechanical integrity to stress fibers following a hyperleongation event in a single stress fiber sarcomere. We also discovered that while these spontaneously occurring hyperelongation events impact single sarcomeres along a stress fiber, they coincide with compensatory shortening in the near-by regions of stress fiber sarcomeres, suggesting there is active remodeling that occurs in actin stress fibers in order to maintain the structure and mechanical homeostasis in live cells. Lastly, we designed a computational model to test whether actin and myosin-based mechanical changes drive some of these dynamic changes in stress fibers. We discovered that variable differences in actin stiffness and myosin contractility may be the main factors in spontaneous changes in iv stress fiber sarcomere length. The findings presented in this dissertation have made exciting contributions to the field of actin cytoskeletal dynamics, and will provide groundwork to future studies dissecting the role of actin-associated proteins in structural and mechanical homeostasis in stress fibers

The Pairing of Trigger Point Dry Needling with Rehabilitation Techniques

Trigger point dry needling is a manual treatment modality used for individuals experiencing tightness, pain, and inhibited range of motion in any region of the body. Dry needling can be described as the insertion of a blunt, microfilament non-medicated needle into the skin for the purpose of targeting specific muscles, which contain tight bands known as trigger points. When the needle is inserted into the trigger point the muscle contracts, holds tight to the needle, and elicits a neural twitch response. This ultimately causes the muscle to relax, allowing for reduction in pain and improvements in range of motion. Although the use of dry needling is rising in popularity in the United States, knowledge of its use and effects is limited. Fortunately, more research is being conducted on this form of treatment. In this thesis, the purpose and physiological effects of dry needling will be discussed in detail, along with a comparison between other alternate medical modalities of treatment which target trigger points. In addition, current research on the effectiveness of incorporating dry needling with other manual therapeutic modalities will be discussed. Dry needling has been shown to be very effective in treating trigger points by improving range of motion, decreasing pain, reducing muscle tightness, and increasing muscle oxygenation. Positive effects of dry needling are even more likely to occur when paired with other modes of therapeutic treatment, often in a physical therapy setting but may also be performed by other health professionals including chiropractors, athletic trainers, occupational therapists, and physicians

The Rheology of Striated Muscles

Striated muscles are actuators of animal bodies. They are responsible for several biomechanical functions critical to survival and these include powering the cardiovascular system and modulating the mechanical interactions the body has with its surroundings. Nearly two centuries of active research on muscle phenomena has led to detailed insights into its microscopic composition, but accurate predictive models of muscle at larger scales remain elusive. This thesis reports on efforts to accurately capture the mechanical properties of striated muscles based on current knowledge of actomyosin dynamics. Specifically, this thesis derives the rheology of striated muscles from the dynamics. Muscle rheology is a characterization of the forces that it develops in resistance to externally imposed changes to its length, i.e. its mechanical behavior as a material. For example, the rheology of elastic solids is stiffness and that of viscous fluids is a damping coefficient. Detailed analyses of actomyosin dynamics suggest that the smallest functional units of striated muscles, half-sarcomeres, are viscoelastic and can function as either a solid-like struct or a fluid-like damper depending on time-durations of interest and neural inputs. Such adaptability may underlie the vastly different biomechanical functions that striated muscles provide to animal bodies. Furthermore, muscles are active structures because their properties require metabolic energy and depend on neural inputs. Striated muscles can therefore exhibit rheologies and functions that elastic springs and viscous fluids cannot. The analysis presented in this thesis may extend beyond muscles and biomedical applications. It may help to engineer muscle-like actuators based on principles of tunable properties and to understand the physics of other materials that can similarly transition between being solid-like and fluid-like

Clinical, Biomechanical, and Physiological Translational Interpretations of Human Resting Myofascial Tone or Tension

Background: Myofascial tissues generate integrated webs and networks of passive and active tensional forces that provide stabilizing support and that control movement in the body. Passive [central nervous system (CNS)–independent] resting myofascial tension is present in the body and provides a low-level stabilizing component to help maintain balanced postures. This property was recently called “human resting myofascial tone” (HRMT). The HRMT model evolved from electromyography (EMG) research in the 1950s that showed lumbar muscles usually to be EMG-silent in relaxed gravity-neutral upright postures. Methods: Biomechanical, clinical, and physiological studies were reviewed to interpret the passive stiffness properties of HRMT that help to stabilize various relaxed functions such as quiet balanced standing. Biomechanical analyses and experimental studies of the lumbar multifidus were reviewed to interpret its passive stiffness properties. The lumbar multifidus was illustrated as the major core stabilizing muscle of the spine, serving an important passive biomechanical role in the body. Results: Research into muscle physiology suggests that passive resting tension (CNS-independent) is generated in sarcomeres by the molecular elasticity of low-level cycling cross-bridges between the actomyosin filaments. In turn, tension is complexly transmitted to intimately enveloping fascial matrix fibrils and other molecular elements in connective tissue, which, collectively, constitute the myofascial unit. Postural myofascial tonus varies with age and sex. Also, individuals in the population are proposed to vary in a polymorphism of postural HRMT. A few people are expected to have outlier degrees of innate postural hypotonicity or hypertonicity. Such biomechanical variations likely predispose to greater risk of related musculoskeletal disorders, a situation that deserves greater attention in clinical practice and research. Axial myofascial hypertonicity was hypothesized to predispose to ankylosing spondylitis. This often-progressive deforming condition of vertebrae and sacroiliac joints is characterized by stiffness features and particular localization of bony lesions at entheseal sites. Such unique features imply concentrations and transmissions of excessive force, leading to tissue micro-injury and maladaptive repair reactions. Conclusions: The HRMT model is now expanded and translated for clinical relevance to therapists. Its passive role in helping to maintain balanced postures is supported by biomechanical principles of myofascial elasticity, tension, stress, stiffness, and tensegrity. Further research is needed to determine the molecular basis of HRMT in sarcomeres, the transmission of tension by the enveloping fascial elements, and the means by which the myofascia helps to maintain efficient passive postural balance in the body. Significant deficiencies or excesses of postural HRMT may predispose to symptomatic or pathologic musculoskeletal disorders whose mechanisms are currently unexplained

The acute effects of stretching on pennation angle and force production

PURPOSE: This study was designed to investigate the acute effects of stretching on pennation angle of the Medial Gastrocnemius and maximal voluntary isotonic plantar flexion. METHODS: 24 healthy college age subjects (14 female, 10 male, age 19-30) completed four trials using a randomized crossover design. Trials consisted of assessing the maximal voluntary isotonic contraction (MVC) and pennation angle (PA) before and after each treatment. Treatments consisted of either stretching (S) or mock stretching (MS). The S treatment involved four 30 second periods of stretching with 15 seconds of rest in between. During the MS treatment subjects were maintained in the same relative position as the S treatment, but were not stretched. RESULTS: There were no significant changes observed in PA from pre to post measurements, though during stretch PA was significantly reduced (p≤0.05). MVC was significantly reduced in the S treatments (p≤0.01). CONCLUSIONS: Stretching had little lasting effect on PA, while MVC was significantly reduced. This finding indicates PA is likely not strongly linked to the MVC reductions observed following stretching

Injury to muscle fibres after single stretches of passive and maximally stimulated muscles in mice.

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110091/1/tjp19954882459.pd

Highly extensible skeletal muscle in snakes

Many snakes swallow large prey whole, and this process requires large displacements of the unfused tips of the mandibles and passive stretching of the soft tissues connecting them. Under these conditions, the intermandibular muscles are highly stretched but subsequently recover normal function. In the highly stretched condition we observed in snakes, sarcomere length (SL) increased 210% its resting value (SL0), and actin and myosin filaments no longer overlapped. Myofibrils fell out of register and triad alignment was disrupted. Following passive recovery, SLs returned to 82% SL0, creating a region of double-overlapping actin filaments. Recovery required recoil of intracellular titin filaments, elastic cytoskeletal components for realigning myofibrils, and muscle activation. Stretch of whole muscles exceeded that of sarcomeres as a result of extension of folded terminal tendon fibrils, stretching of extracellular elastin and independent slippage of muscle fibers. Snake intermandibular muscles thus provide a unique model of how basic components of vertebrate skeletal muscle can be modified to permit extreme extensibility. © 2014. Published by The Company of Biologists Ltd