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Skeletal Muscle Myofilament Adaptations To Aging, Disease And Disuse And Their Effects On Whole Muscle Performance In Older Adult Humans, Mark S. Miller, Damien M. Callahan, Michael J. Toth
Skeletal Muscle Myofilament Adaptations To Aging, Disease And Disuse And Their Effects On Whole Muscle Performance In Older Adult Humans, Mark S. Miller, Damien M. Callahan, Michael J. Toth
Mark S. Miller
Skeletal muscle contractile function declines with aging, disease, and disuse. In vivo muscle contractile function depends on a variety of factors, but force, contractile velocity and power generating capacity ultimately derive from the summed contribution of single muscle fibers. The contractile performance of these fibers are, in turn, dependent upon the isoform and function of myofilament proteins they express, with myosin protein expression and its mechanical and kinetic characteristics playing a predominant role. Alterations in myofilament protein biology, therefore, may contribute to the development of functional limitations and disability in these conditions. Recent studies suggest that these conditions are associated …
An Inverse Power-Law Distribution Of Molecular Bond Lifetimes Predicts Fractional Derivative Viscoelasticity In Biological Tissue, Bradley M. Palmer, Bertrand C.W. Tanner, Michael J. Toth, Mark S. Miller
An Inverse Power-Law Distribution Of Molecular Bond Lifetimes Predicts Fractional Derivative Viscoelasticity In Biological Tissue, Bradley M. Palmer, Bertrand C.W. Tanner, Michael J. Toth, Mark S. Miller
Mark S. Miller
Viscoelastic characteristics of many materials falling under the category of soft glassy substances, including biological tissue, often exhibit a mechanical complex modulus Y(ω) well described by a fractional derivative model: Y(ω) = E(ίω/ø)k, where E = a generalized viscoelastic stiffness; i = (-1)1/2; ω = angular frequency; ø =- scaling factor; and k = an exponent valued between 0 and 1. The term ‘‘fractional derivative’’ refers to the value of k: when k = 0 the viscoelastic response is purely elastic, and when k = 1 the response is purely viscous. We provide an analytical derivation of the fractional derivative …
Thick-To-Thin Filament Surface Distance Modulates Cross-Bridge Kinetics In Drosophila Flight Muscle, Bertrand C.W. Tanner, Gerrie P. Farman, Thomas C. Irving, David W. Maughan, Bradley M. Palmer, Mark S. Miller
Thick-To-Thin Filament Surface Distance Modulates Cross-Bridge Kinetics In Drosophila Flight Muscle, Bertrand C.W. Tanner, Gerrie P. Farman, Thomas C. Irving, David W. Maughan, Bradley M. Palmer, Mark S. Miller
Mark S. Miller
The demembranated (skinned) muscle fiber preparation is widely used to investigate muscle contraction because the intracellular ionic conditions can be precisely controlled. However, plasma membrane removal results in a loss of osmotic regulation, causing abnormal hydration of the myofilament lattice and its proteins. We investigated the structural and functional consequences of varied myofilament lattice spacing and protein hydration on cross-bridge rates of force development and detachment in Drosophila melanogaster indirect flight muscle, using x-ray diffraction to compare the lattice spacing of dissected, osmotically compressed skinned fibers to native muscle fibers in living flies. Osmolytes of different sizes and exclusion properties …
Resistance Training Alters Skeletal Muscle Structure And Function In Human Heart Failure: Effects At The Tissue, Cellular And Molecular Levels, Michael J. Toth, Mark S. Miller, Peter Vanburen, Nicholas G. Bedrin, Martin M. Lewinter, Philip A. Ades, Bradley M. Palmer
Resistance Training Alters Skeletal Muscle Structure And Function In Human Heart Failure: Effects At The Tissue, Cellular And Molecular Levels, Michael J. Toth, Mark S. Miller, Peter Vanburen, Nicholas G. Bedrin, Martin M. Lewinter, Philip A. Ades, Bradley M. Palmer
Mark S. Miller
Reduced skeletal muscle function in heart failure (HF) patients may be partially explained by altered myofilament protein content and function. Resistance training increases muscle function, although whether these improvements are achieved by correction of myofilament deficits is not known. To address this question, we examined 10 HF patients and 14 controls prior to and following an 18 week high-intensity resistance training programme. Evaluations of wholemuscle size and strength, singlemuscle fibre size, ultrastructure and tension andmyosin–actin cross-bridge mechanics and kineticswere performed. Training improved whole muscle isometric torque in both groups, although therewere no alterations in wholemuscle size or single fibre cross-sectional …
Distribution Of Myosin Attachment Times Predicted From Viscoelasticmechanics Of Striatedmuscle, Bradley M. Palmer, Yuan Wang, Mark S. Miller
Distribution Of Myosin Attachment Times Predicted From Viscoelasticmechanics Of Striatedmuscle, Bradley M. Palmer, Yuan Wang, Mark S. Miller
Mark S. Miller
We demonstrate that viscoelastic mechanics of striated muscle, measured as elastic and viscous moduli, emerge directly from the myosin crossbridge attachment time, tatt, also called time-on. The distribution of tatt was modeled using a gamma distribution with shape parameter, p, and scale parameter, β. At 5mM MgATP, β was similar between mouse α-MyHC (16.0 ± 3.7ms) and β-MyHC (17.9 ± 2.0ms), and p was higher (P < 0.05) for β-MyHC (5.6 ± 0.4 no units) compared to α-MyHC (3.2 ± 0.9). At 1mMMgATP, p approached a value of 10 in both isoforms, but β rose only in the β-MyHC (34.8 ± 5.8ms). The estimated mean tatt (i.e., pβ product) was longer in the β-MyHC compared to α-MyHC, and became prolonged in both isoforms as MgATP was reduced as expected. The application of our viscoelastic model to these isoforms and varying MgATP conditions suggest that tatt is better modeled as a gamma distribution due to its representing multiple temporal events occurring within tatt compared to a single exponential distribution which assumes only one temporal event within tatt.
Effect Of Resistance Training On Physical Disability In Chronic Heart Failure, Patrick Savage, Anthony O. Shaw, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, Philip A. Ades, Michael J. Toth
Effect Of Resistance Training On Physical Disability In Chronic Heart Failure, Patrick Savage, Anthony O. Shaw, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, Philip A. Ades, Michael J. Toth
Mark S. Miller
Purpose—Patients with chronic heart failure (CHF) report difficulty performing activities of daily living. To our knowledge, however, no study has directly measured performance in activities of daily living in these patients to systematically assess their level of physical disability. Moreover, the contribution of skeletal muscle weakness to physical disability in CHF remains unclear. Thus, we measured performance in activities of daily living in CHF patients and controls, its relationship to aerobic capacity and muscle strength and the effect of resistance exercise training to improve muscle strength and physical disability. Methods—Patients and controls were assessed for performance in activities of daily …
Cooh-Terminal Truncation Of Flightin Decreases Myofilament Lattice Organization, Cross-Bridge Binding, And Power Output Indrosophila Indirect Flight Muscle, Bertrand C.W. Tanner, Mark S. Miller, Becky M. Miller, Panagiotis Lekkas, Thomas C. Irving, David W. Maughan, Jim O. Vigoreaux
Cooh-Terminal Truncation Of Flightin Decreases Myofilament Lattice Organization, Cross-Bridge Binding, And Power Output Indrosophila Indirect Flight Muscle, Bertrand C.W. Tanner, Mark S. Miller, Becky M. Miller, Panagiotis Lekkas, Thomas C. Irving, David W. Maughan, Jim O. Vigoreaux
Mark S. Miller
IN MUSCLE, THE THICK AND THIN filament lattice provides the structural and mechanical foundation for transmitting contractile forces throughout the cell. The highly ordered indirect flight muscle (IFM) of Drosophila melanogaster is an attractive model system to study the relationship between lattice structure and muscle function, because its in vivo lattice organization can be measured via X-ray diffraction in living flies (15) and its function can be measured from the whole fly to the molecule (14, 20, 30). In addition, the means for producing genetic alterations of specific proteins in D. melanogaster are well established, permitting precise manipulation of thick …
Regulatory Light Chain Phosphorylation And N-Terminal Extension Increase Cross-Bridge Binding And Power Output In Drosophila At In Vivo Myofilament Lattice Spacing, Mark S. Miller, Gerrie P. Farman, Joan M. Braddock, Felipe N. Soto-Adames, Thomas C. Ivring, Jim O. Vigoreaux, David W. Maughan
Regulatory Light Chain Phosphorylation And N-Terminal Extension Increase Cross-Bridge Binding And Power Output In Drosophila At In Vivo Myofilament Lattice Spacing, Mark S. Miller, Gerrie P. Farman, Joan M. Braddock, Felipe N. Soto-Adames, Thomas C. Ivring, Jim O. Vigoreaux, David W. Maughan
Mark S. Miller
The N-terminal extension and phosphorylation of the myosin regulatory light chain (RLC) independently improve Drosophila melanogaster flight performance. Here we examine the functional and structural role of the RLC in chemically skinned fibers at various thick and thin filament lattice spacings from four transgenic Drosophila lines: rescued null or control (Dmlc2þ), truncated N-terminal extension (Dmlc2D2-46), disrupted myosin light chain kinase phosphorylation sites (Dmlc2S66A,S67A), and dual mutant (Dmlc2D2-46; S66A,S67A). The N-terminal extension truncation and phosphorylation sites disruption mutations decreased oscillatory power output and the frequency of maximum power output in maximally Ca2+-activated fibers compressed to near in vivo inter-thick filament spacing, …
Reduced Knee Extensor Function In Heart Failure Is Not Explained By Inactivity, Michael J. Toth, Anthony O. Shaw, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, David W. Maughan, Philip A. Ades
Reduced Knee Extensor Function In Heart Failure Is Not Explained By Inactivity, Michael J. Toth, Anthony O. Shaw, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, David W. Maughan, Philip A. Ades
Mark S. Miller
Background—The goal of this study was to determine if heart failure alters knee extensor muscle torque, power production or contractile velocity. Methods—Heart failure patients (n=11; 70.4 ± 4.3 yrs) and controls (n=11; 70.3 ± 3.4 yrs) matched for age and sex were evaluated for knee extensor contractile performance under isometric and isokinetic conditions and body composition by dual energy x-ray absorptiometry. Additionally, we recruited sedentary to minimally active elderly controls to match heart failure patients for habitual physical activity and assessed activity levels using accelerometry. Results—Groups did not differ for total or regional body composition or average daily physical activity …
Comparative Biomechanics Of Thick Filaments And Thin Filaments With Functional Consequences Formuscle Contraction, Mark S. Miller, Bertrand C.W. Tanner, Lori R. Nyland, Jim O. Vigoreaux
Comparative Biomechanics Of Thick Filaments And Thin Filaments With Functional Consequences Formuscle Contraction, Mark S. Miller, Bertrand C.W. Tanner, Lori R. Nyland, Jim O. Vigoreaux
Mark S. Miller
The scaffold of striated muscle is predominantly comprised of myosin and actin polymers known as thick filaments and thin filaments, respectively. The roles these filaments play in muscle contraction are well known, but the extent to which variations in filament mechanical properties influence muscle function is not fully understood. Here we review information on the material properties of thick filaments, thin filaments, and their primary constituents; we also discuss ways in which mechanical properties of filaments impact muscle performance.
Phosphorylation And The N-Terminal Extension Of The Regulatory Light Chain Help Orient And Align The Myosin Heads In Drosophila Flight Muscle, Gerrie Farman, Mark Miller, Mary Reedy, Felipe Soto-Adames, Jim Vigoreaux, David Maughan, Thomas Irving
Phosphorylation And The N-Terminal Extension Of The Regulatory Light Chain Help Orient And Align The Myosin Heads In Drosophila Flight Muscle, Gerrie Farman, Mark Miller, Mary Reedy, Felipe Soto-Adames, Jim Vigoreaux, David Maughan, Thomas Irving
Mark S. Miller
X-ray diffraction of the indirect flight muscle (IFM) in living Drosophila at rest and electron microscopy of intact and glycerinated IFM was used to compare the effects of mutations in the regulatory light chain (RLC) on sarcomeric structure. Truncation of the RLC N-terminal extension (Dmlc2Δ2-46) or disruption of the phosphorylation sites by substituting alanines (Dmlc2S66A, S67A) decreased the equatorial intensity ratio (I20/I10), indicating decreased myosin mass associated with the thin filaments. Phosphorylation site disruption (Dmlc2S66A, S67A), but not N-terminal extension truncation (Dmlc2Δ2-46), decreased the 14.5 nm reflection intensity, indicating a spread of the axial distribution of the myosin heads. The …
Mechanisms Underlying Skeletal Muscle Weakness In Human Heart Failure: Alterations In Single Fiber Myosin Protein Content And Function, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, Stewart H. Lecker, Donald E. Selby, Bradley M. Palmer, David W. Maughan, Philip A. Ades, Michael J. Toth
Mechanisms Underlying Skeletal Muscle Weakness In Human Heart Failure: Alterations In Single Fiber Myosin Protein Content And Function, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, Stewart H. Lecker, Donald E. Selby, Bradley M. Palmer, David W. Maughan, Philip A. Ades, Michael J. Toth
Mark S. Miller
Background—Patients suffering from chronic heart failure frequently experience skeletal muscle weakness, which limits physical function. The mechanisms underlying muscle weakness, however, have not been clearly defined. Methods and Results—The present study examined the hypothesis that heart failure promotes a loss of myosin protein from single skeletal muscle fibers, which in turn reduces contractile performance. Ten patients with chronic heart failure and 10 controls were studied. Muscle atrophy was not evident in patients, and groups displayed similar physical activity levels, suggesting that observed differences reflect the effects of heart failure, not muscle atrophy or disuse. In single muscle fibers, heart failure …
Alternative S2 Hinge Regions Of The Myosin Rod Affect Myofibrillar Structure And Myosin Kinetics, Mark S. Miller, Corey M. Dambacher, Aileen F. Knowles, Joan M. Braddock, Gerrie P. Farman, Thomas C. Irving, Douglas M. Swank, Sanford I. Bernstein, David W. Maughan
Alternative S2 Hinge Regions Of The Myosin Rod Affect Myofibrillar Structure And Myosin Kinetics, Mark S. Miller, Corey M. Dambacher, Aileen F. Knowles, Joan M. Braddock, Gerrie P. Farman, Thomas C. Irving, Douglas M. Swank, Sanford I. Bernstein, David W. Maughan
Mark S. Miller
The subfragment 2/light meromyosin ‘‘hinge’’ region has been proposed to significantly contribute to muscle contraction force and/or speed. Transgenic replacement of the endogenous fast muscle isovariant hinge A (exon 15a) in Drosophila melanogaster indirect flight muscle with the slow muscle hinge B (exon 15b) allows examination of the structural and functional changes when only this region of the myosin molecule is different. Hinge B was previously shown to increase myosin rod length, increase A-band and sarcomere length, and decrease flight performance compared to hinge A. We applied additional measures to these transgenic lines to further evaluate the consequences of modifying …
Aging Enhances Indirect Flight Muscle Fiber Performance Yet Decreases Flight Ability In Drosophila, Mark S. Miller, Panagiotis Lekkas, Joan M. Braddock, Gerrie P. Farman, Bryan A. Ballif, Thomas C. Irving, David W. Maughan, Jim O. Vigoreaux
Aging Enhances Indirect Flight Muscle Fiber Performance Yet Decreases Flight Ability In Drosophila, Mark S. Miller, Panagiotis Lekkas, Joan M. Braddock, Gerrie P. Farman, Bryan A. Ballif, Thomas C. Irving, David W. Maughan, Jim O. Vigoreaux
Mark S. Miller
We investigated the effects of aging on Drosophila melanogaster indirect flight muscle from the whole organism to the actomyosin cross-bridge. Median-aged (49-day-old) flies were flight impaired, had normal myofilament number and packing, barely longer sarcomeres, and slight mitochondrial deterioration compared with young (3-day-old) flies. Old (56-dayold) flies were unable to beat their wings, had deteriorated ultrastructure with severe mitochondrial damage, and their skinned fibers failed to activate with calcium. Small-amplitude sinusoidal length perturbation analysis showed median-aged indirect flight muscle fibers developed greater than twice the isometric force and power output of young fibers, yet cross-bridge kinetics were similar. Large increases …
Two-State Model Of Acto-Myosin Attachment-Detachment Predicts C-Process Of Sinusoidal Analysis, Bradley M. Palmer, Takeki Suzuki, Yuan Wang, William D. Barnes, Mark S. Miller, David W. Maughan
Two-State Model Of Acto-Myosin Attachment-Detachment Predicts C-Process Of Sinusoidal Analysis, Bradley M. Palmer, Takeki Suzuki, Yuan Wang, William D. Barnes, Mark S. Miller, David W. Maughan
Mark S. Miller
The force response of activated striated muscle to length perturbations includes the so-called C-process, which has been considered the frequency domain representation of the fast single-exponential force decay after a length step (phases 1 and 2). The underlying molecular mechanisms of this phenomenon, however, are still the subject of various hypotheses. In this study, we derived analytical expressions and created a corresponding computer model to describe the consequences of independent acto-myosin cross-bridges characterized solely by 1), intermittent periods of attachment (t(att)) and detachment (t(det)), whose values are stochastically governed by independent probability density functions; and 2), a finite Hookian stiffness …
Passive Stiffness In Drosophila Indirect Flight Muscle Reduced By Disrupting Paramyosin Phosphorylation, But Not By Embryonic Myosin S2 Hinge Substitution, Yudong Hao, Mark S. Miller, Douglas M. Swank, Hongjun Liu, Sanford I. Bernstein, David W. Maughan, Gerald H. Pollack
Passive Stiffness In Drosophila Indirect Flight Muscle Reduced By Disrupting Paramyosin Phosphorylation, But Not By Embryonic Myosin S2 Hinge Substitution, Yudong Hao, Mark S. Miller, Douglas M. Swank, Hongjun Liu, Sanford I. Bernstein, David W. Maughan, Gerald H. Pollack
Mark S. Miller
High passive stiffness is one of the characteristic properties of the asynchronous indirect flight muscle (IFM) found in many insects like Drosophila. To evaluate the effects of two thick filament protein domains on passive sarcomeric stiffness, and to investigate their correlation with IFM function, we used microfabricated cantilevers and a high resolution imaging system to study the passive IFM myofibril stiffness of two groups of transgenic Drosophila lines. One group (hinge-switch mutants) had a portion of the endogenous S2 hinge region replaced by an embryonic version; the other group (paramyosin mutants) had one or more putative phosphorylation sites near the …
Paramyosin Phosphorylation Site Disruption Affects Indirect Flight Muscle Stiffness And Power Generation In Drosophila Melanogaster, Hongjun Liu, Mark S. Miller, Douglas M. Swank, William A. Kronert, David W. Maughan, Sanford I. Bernstein
Paramyosin Phosphorylation Site Disruption Affects Indirect Flight Muscle Stiffness And Power Generation In Drosophila Melanogaster, Hongjun Liu, Mark S. Miller, Douglas M. Swank, William A. Kronert, David W. Maughan, Sanford I. Bernstein
Mark S. Miller
The phosphoprotein paramyosin is a major structural component of invertebrate muscle thick filaments. To investigate the importance of paramyosin phosphorylation, we produced transgenic Drosophila melanogaster in which one, three, or four phosphorylatable serine residues in the N-terminal nonhelical domain were replaced by alanines. Depending on the residues mutated, transgenic lines were either unaffected or severely flight impaired. Flight-impaired strains had decreases in the most acidic paramyosin isoforms, with a corresponding increase in more basic isoforms. Surprisingly, ultrastructure of indirect flight muscle myofibrils was normal, indicating N-terminal phosphorylation is not important for myofibril assembly. However, mechanical studies of active indirect flight …
Molecular Mechanisms Underlying Skeletal Muscle Weakness In Human Cancer: Reduced Myosin-Actin Cross-Bridge Formation And Kinetics, Michael Jj. Toth, Mark S. Miller, Damien M. Callahan, Andrew P. Sweeny, Ivette Nunez, Steven M. Grunberg, Hirak Der-Torossian, Marion E. Couch, Kim Dittus
Molecular Mechanisms Underlying Skeletal Muscle Weakness In Human Cancer: Reduced Myosin-Actin Cross-Bridge Formation And Kinetics, Michael Jj. Toth, Mark S. Miller, Damien M. Callahan, Andrew P. Sweeny, Ivette Nunez, Steven M. Grunberg, Hirak Der-Torossian, Marion E. Couch, Kim Dittus
Mark S. Miller
PHYSICAL FUNCTION DETERIORATES substantially following a diagnosis of cancer (3, 48), and patients view this decline as one of the most distressing side effects of the disease, more so than classic side effects such as pain, nausea, and vomiting (13, 60). Functional disability can be the impetus for dose reduction or cessation of anticancer treatments and predicts chemotherapy toxicity and survival (12, 30, 33, 39). Our current understanding of the factors contributing to reduced functional capacity in patients with cancer is, however, severely limited. Physiological changes that occur within the skeletal muscle of patients with cancer can contribute to functional …
Skeletal Muscle Mitochondrial Density, Gene Expression, And Enzyme Activities In Human Heart Failure: Minimal Effects Of The Disease And Resistance Training, Michael J. Toth, Mark S. Miller, Kimberly A. Ward, Philip A. Ades
Skeletal Muscle Mitochondrial Density, Gene Expression, And Enzyme Activities In Human Heart Failure: Minimal Effects Of The Disease And Resistance Training, Michael J. Toth, Mark S. Miller, Kimberly A. Ward, Philip A. Ades
Mark S. Miller
IMPAIRED SKELETAL MUSCLE ENERGETICS in heart failure (HF) patients (32) may contribute to physical disability and metabolic dysfunction. Decreased skeletal muscle oxidative capacity (63), secondary to reduced mitochondrial density (12, 13) and/or function (10, 36, 52), may contribute to exercise intolerance, the hallmark symptom of HF. Moreover, as mitochondrial dysfunction is associated with fiber atrophy (7), impaired energetics may reduce physical function by promoting muscle wasting and, in turn, weakness (21). Because mitochondrial dysfunction has been implicated in the pathophysiology of diabetes (41), alterations in mitochondrial content and/or function could also contribute to the high prevalence of insulin resistance in …
Chronic Heart Failure Reduces Akt Phosphorylation In Human Skeletal Muscle: Relationship To Muscle Size And Function, Michael J. Toth, Kimberly Ward, Jos Van Der Velden, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, Philip A. Ades
Chronic Heart Failure Reduces Akt Phosphorylation In Human Skeletal Muscle: Relationship To Muscle Size And Function, Michael J. Toth, Kimberly Ward, Jos Van Der Velden, Mark S. Miller, Peter Vanburen, Martin M. Lewinter, Philip A. Ades
Mark S. Miller
HEART FAILURE (HF) is the final common pathway for many chronic cardiac diseases and is presently the only cardiac diagnosis continuing to increase in prevalence in the United States. Patients suffering from HF report high rates of physical disability, as defined by an inability to perform simple daily activities (43). Although the reason for their physical disability is unclear, most research has focused on aerobic exercise intolerance in these patients (23). This is logical considering that the hallmark symptom of HF is exertional dyspnea and because of the widespread use of aerobic capacity as a diagnostic tool (36). Diminished aerobic …