Skeletal muscle design studies, based on anatomical structure, extend back several hundred years. Accurate anatomical drawings show that many muscle fibers are oriented at an angle relative to a ...muscle’s axis of force generation. This pennation angle has been reported in the skeletal muscle biomechanics literature, primarily in the context of trying to understand muscle force generation. In this perspective, I will describe several discoveries that changed my understanding of pennation and I will suggest that muscle pennation has little if any functional significance. I believe that the correct view of pennation is that it represents a packing strategy whereby short fibers can be packed into a limited volume. While surface pennation angle is easily measured, is very descriptive, and changes during force generation, I believe it has no functional significance.
The skeletal muscle extracellular matrix (ECM) plays an important role in muscle fiber force transmission, maintenance, and repair. In both injured and diseased states, ECM adapts dramatically, a ...property that has clinical manifestations and alters muscle function. Here we review the structure, composition, and mechanical properties of skeletal muscle ECM; describe the cells that contribute to the maintenance of the ECM; and, finally, overview changes that occur with pathology. New scanning electron micrographs of ECM structure are also presented with hypotheses about ECM structure–function relationships. Detailed structure–function relationships of the ECM have yet to be defined and, as a result, we propose areas for future study. Muscle Nerve 44: 318–331, 2011
Skeletal muscle fibrosis can be a devastating clinical problem that arises from many causes, including primary skeletal muscle tissue diseases, as seen in the muscular dystrophies, or it can be ...secondary to events that include trauma to muscle or brain injury. The cellular source of activated fibroblasts (myofibroblasts) may include resident fibroblasts, adult muscle stem cells, or inflammatory or perivascular cells, depending on the model studied. Even though it is likely that there is no single source for all myofibroblasts, a common mechanism for the production of fibrosis is via the transforming growth factor-β/phosphorylated Smad3 pathway. This pathway and its downstream targets thus provide loci for antifibrotic therapies, as do methods for blocking the transdifferentiation of progenitors into activated fibroblasts. A structural model for the extracellular collagen network of skeletal muscle is needed so that measurements of collagen content, morphology, and gene expression can be related to mechanical properties. Approaches used to study fibrosis in tissues, such as lung, kidney, and liver, need to be applied to studies of skeletal muscle to identify ways to prevent or even cure the devastating maladies of skeletal muscle.
Skeletal muscle contractures represent the permanent shortening of a muscle-tendon unit, resulting in loss of elasticity and, in extreme cases, joint deformation. They may result from cerebral palsy, ...spinal cord injury, stroke, muscular dystrophy, and other neuromuscular disorders. Contractures are the prototypic and most severe clinical presentation of increased passive mechanical muscle force in humans, often requiring surgical correction. Intraoperative experiments demonstrate that high muscle passive force is associated with sarcomeres that are abnormally stretched, although otherwise normal, with fewer sarcomeres in series. Furthermore, changes in the amount and arrangement of collagen in the extracellular matrix also increase muscle stiffness. Structural light and electron microscopy studies demonstrate that large bundles of collagen, referred to as perimysial cables, may be responsible for this increased stiffness and are regulated by interaction of a number of cell types within the extracellular matrix. Loss of muscle satellite cells may be related to changes in both sarcomeres and extracellular matrix. Future studies are required to determine the underlying mechanism for changes in muscle satellite cells and their relationship (if any) to contracture. A more complete understanding of this mechanism may lead to effective nonsurgical treatments to relieve and even prevent muscle contractures.
There Must Be a Better Way Lieber, Richard L
Journal of bone and joint surgery. American volume,
06/2023, Letnik:
105, Številka:
12
Journal Article
Recenzirano
The National Institutes of Health (NIH) R01 grant represents the gold standard for research independence across the United States. The barrier to entry for this grant mechanism is extremely high, ...with <10% of grants being funded. Interestingly, after this tremendously high barrier, there is very little accountability for the grantee to accomplish the aims that were originally proposed. While there is certainly value to requiring investigators to provide a logical and compelling research plan, excessive grant writing creates a large inefficiency. Thus, a "fail quickly" model, which is not without cost, should be considered. Such a model involves a much lower barrier to entry and much higher short-term accountability so that more aims can be tested in less time at lower cost.
Skeletal muscle design to meet functional demands Lieber, Richard L.; Ward, Samuel R.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
05/2011, Letnik:
366, Številka:
1570
Journal Article
Recenzirano
Odprti dostop
Skeletal muscles are length- and velocity-sensitive force producers, constructed of a vast array of sarcomeres. Muscles come in a variety of sizes and shapes to accomplish a wide variety of tasks. ...How does muscle design match task performance? In this review, we outline muscle's basic properties and strategies that are used to produce movement. Several examples are provided, primarily for human muscles, in which skeletal muscle architecture and moment arms are tailored to a particular performance requirement. In addition, the concept that muscles may have a preferred sarcomere length operating range is also introduced. Taken together, the case is made that muscles can be fine-tuned to perform specific tasks that require actuators with a wide range of properties.
Differences in passive muscle mechanical properties between amphibians and mammals have led to differing hypotheses on the functional role of titin in skeletal muscle. Early studies of frog muscle ...clearly demonstrated intracellular load bearing by titin, but more recent structural and biological studies in mice have shown that titin may serve other functions. Here, we present biomechanical studies of isolated frog and mouse fibers, and fiber bundles to compare the relative importance of intracellular versus extracellular load bearing in these species. Mouse bundles exhibited increased modulus compared with fibers on the descending limb of the length-tension curve, reaching a 2.4-fold elevation at the longest sarcomere lengths. By contrast, frog fibers and bundles had approximately the same modulus at all sarcomere lengths tested. These findings suggest that in the mouse, both muscle fibers and the ECM are involved in bearing whole muscle passive tension, which is distinct from the load bearing process in frog muscle, where titin bears the majority of whole muscle passive tension.
Computer models that estimate the force generation capacity of lower limb muscles have become widely used to simulate the effects of musculoskeletal surgeries and create dynamic simulations of ...movement. Previous lower limb models are based on severely limited data describing limb muscle architecture (i.e., muscle fiber lengths, pennation angles, and physiological cross-sectional areas). Here, we describe a new model of the lower limb based on data that quantifies the muscle architecture of 21 cadavers. The model includes geometric representations of the bones, kinematic descriptions of the joints, and Hill-type models of 44 muscle–tendon compartments. The model allows calculation of muscle–tendon lengths and moment arms over a wide range of body positions. The model also allows detailed examination of the force and moment generation capacities of muscles about the ankle, knee, and hip and is freely available at
www.simtk.org
.
The vast majority of skeletal muscle biomechanical studies have rightly focused on its active contractile properties. However, skeletal muscle passive biomechanical properties have significant ...clinical impact in aging and disease and are yet incompletely understood. This review focuses on the passive biomechanical properties of the skeletal muscle extracellular matrix (ECM) and suggests aspects of its structural basis. Structural features of the muscle ECM such as perimysial cables, collagen cross-links and endomysial structures have been described, but the way in which these structures combine to create passive biomechanical properties is not completely known. We highlight the presence and organization of perimysial cables. We also demonstrate that the analytical approaches that define passive biomechanical properties are not necessarily straight forward. For example, multiple equations, such as linear, exponential, and polynomial are commonly used to fit raw stress–strain data. Similarly, multiple definitions of zero strain exist that affect muscle biomechanical property calculations. Finally, the appropriate length range over which to measure the mechanical properties is not clear. Overall, this review summarizes our current state of knowledge in these areas and suggests experimental approaches to measuring the structural and functional properties of skeletal muscle.
Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by ...facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection.
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