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Total knee arthroplasty (TKA) is an important treatment option for knee osteoarthritis (OA) that improves self-reported pain and physical function, but objectively measured physical function typically remains reduced for years after surgery due, in part, to precipitous reductions in lower extremity neuromuscular function early after surgery. The present study examined intrinsic skeletal muscle adaptations during the first 5 weeks post-TKA to identify skeletal muscle attributes that may contribute to functional disability. Patients with advanced stage knee OA were evaluated prior to TKA and 5 weeks after surgery. Biopsies of the vastus lateralis were performed to assess muscle fiber size, contractility, and mitochondrial content, along with assessments of whole muscle size and function. TKA was accompanied by marked reductions in whole muscle size and strength. At the fiber (i.e., cellular) level, TKA caused profound muscle atrophy that was approximately twofold higher than that observed at the whole muscle level. TKA markedly reduced muscle fiber force production, contractile velocity, and power production, with force deficits persisting in myosin heavy chain (MHC) II fibers after expression relative to fiber size. Molecular level assessments suggest reduced strongly bound myosin-actin cross bridges and myofilament lattice stiffness as a mechanism underlying reduced force per unit fiber size. Finally, marked reductions in mitochondrial content were apparent and more prominent in the subsarcolemmal compartment. Our study represents the most comprehensive evaluation of skeletal muscle cellular adaptations to TKA and uncovers novel effects of TKA on muscle fiber size and intrinsic contractility early after surgery that may contribute to functional disability.

Background: Anterior cruciate ligament (ACL) trauma and ACL reconstruction (ACLR) are associated with the loss of strength and function of the muscles that span the knee joint. The underlying mechanism associated with this is not completely understood. Purpose: To determine whether the duration of tourniquet use during ACLR has an effect on knee extensor muscle contractile function and size at the cellular (ie, fiber) level 3 weeks after surgery and at the whole-muscle level at 6 months after surgery. Study Design: Descriptive laboratory study and case series; Level of evidence, 4. Methods: Study participants sustained an acute, first-time ACL injury. All participants underwent ACLR with the use of a tourniquet placed in a standardized location on the thigh; the tourniquet was inflated (pressure range, 250-275 mm Hg), and the time of tourniquet use during surgery was documented. Participants were evaluated 1 week before surgery (to measure patient function, strength, and subjective outcome with the Knee injury and Osteoarthritis Outcome Score [KOOS] and International Knee Documentation Committee [IKDC] score), at 3 weeks after ACLR surgery (to obtain muscle biopsy specimens of the vastus lateralis and assess muscle fiber cross-sectional area, contractile function, and mitochondrial content and morphometry), and at 6 months after ACLR (to evaluate patient function, strength, and subjective outcomes via KOOS and IKDC scores). Data were acquired on both the injured/surgical limb and the contralateral, normal side to facilitate the use of a within-subjects study design. Results are based on additional analysis of data acquired from previous research that had common entry criteria, treatments, and follow-up protocols. Results: At 3 weeks after ACLR, the duration of tourniquet use at the time of surgery did not explain the variation in single–muscle fiber contractile function or cross-sectional area (myosin heavy chain [MHC] I and II fibers) or subsarcolemmal and intermyofibrillar mitochondrial content or morphometry. At 6 months after ACLR, the duration of tourniquet use was not associated with the peak isometric and isokinetic torque measurements, patient function, or patient-reported outcomes. Conclusion: The duration of tourniquet use at the time of ACLR surgery did not explain variation in muscle fiber size, contractile function, or mitochondrial content at 3 weeks after surgery or strength of the quadriceps musculature or patient-reported function or quality of life at 6-month follow-up.

Loss of quadriceps strength after total knee arthroplasty (TKA) is most pronounced acutely but persists long-term, negatively impacting physical function in daily activities. Neuromuscular electrical stimulation (NMES) early after surgery is an effective adjuvant to standard of care rehabilitation (SOC) for attenuating strength loss following TKA, but the mechanisms whereby NMES maintains strength are unclear. This work aimed to determine the effects of early NMES on quadriceps strength and skeletal muscle fiber size 2 weeks after TKA compared to SOC. Patients scheduled for primary, unilateral TKA were enrolled and randomized into SOC (n = 9) or NMES plus SOC (n = 10) groups. NMES was started within 48 h of TKA, with 45-min sessions twice a day for 2 weeks. Isometric quadriceps strength was assessed preoperatively and 2 weeks following TKA. Vastus lateralis muscle biopsies of the involved leg were performed at the same time points and immunohistochemistry conducted to assess muscle fiber cross-sectional area and distinguish fiber types. Groups did not differ in age, body mass index, sex distribution, or preoperative strength. Both groups got weaker postoperatively, but the NMES group had higher normalized strength. After 2 weeks, the group receiving NMES and SOC had significantly greater MHC IIA and MHC IIA/IIX fiber size compared to SOC alone, with no group differences in MHC I fiber size. These results suggest that NMES mitigates early muscle weakness following TKA, in part, via effects on fast-twitch, type II muscle fiber size. This investigation advances our understanding of how adjuvant, early postoperative NMES aids muscle strength recovery.

Muscle dysfunction following anterior cruciate ligament reconstruction (ACLR) may evolve from alterations in muscle contractility at the myofilament protein level. Using a prospective, within-subject case control design, we evaluated cellular-level contractility, cross-sectional area (CSA), and myosin heavy chain (MHC) isoform expression on single muscle fibers 3-weeks post ACLR, and evaluated their relationship to whole muscle strength and patient-oriented outcomes 6 months post-op. Biopsies of the vastus lateralis were performed 3-weeks post-ACLR in 11 subjects (5 female, mean age ±SD = 24.7 ± 6.5 yr, height = 172.7 ± 8.2 cm, mass = 75.7 ± 12.5 kg) following first-time ACL rupture and whole muscle strength and self-reported pain, function, and quality of life assessed 6-months post-ACLR. At 3-weeks post ACLR, force production was reduced (P

PURPOSE Coronary artery bypass graft (CABG) surgery is an important treatment option in patients with coronary artery disease. Despite its beneficial effects, CABG surgery and its subsequent hospitalization may reduce physical functional capacity in patients, contributing to physical disability. Our objective was to assess the early disabling effects of CABG surgery and its subsequent hospitalization using direct measurements of physical function. METHODS Patients (n = 44) were assessed pre-surgery and at hospital discharge for physical function using the Short Physical Performance Battery (SPPB) and self-reported physical and mental health by questionnaire. RESULTS The total SPPB score (P < .001) and all of its components (P < .01-.001) decreased markedly following CABG surgery and hospitalization, with greater reductions in total SPPB score (P < .05) and gait speed (P < .01) in patients with higher body mass index. While CABG surgery and hospitalization reduced patient-reported physical function, changes in these indices largely did not correlate with changes in SPPB outcomes. CONCLUSION Our results show the early disabling effects of CABG surgery and hospitalization on directly measured physical function, and that patients with higher body mass index had greater reductions. In addition, our results underscore the need to perform direct measurements of physical function to describe reductions in physiological functional capacity. These findings suggest the need for inpatient rehabilitation or early mobility programs to address this decline in physical function. ABSTRACT FOR TOC This is the first study to evaluate the early disabling effects of coronary artery bypass graft surgery and hospitalization using direct measures of physical function. Although self-reported physical function also decreased, these changes largely did not correlate with direct measures of physical function.

PURPOSE Cardiorespiratory and skeletal muscle deconditioning occurs following coronary artery bypass graft surgery and hospitalization. Outpatient, phase 2 cardiac rehabilitation (CR) is designed to remediate this deconditioning but typically does not begin until several weeks following hospital discharge. Although an exercise program between discharge and the start of CR could improve functional recovery, implementation of exercise at this time is complicated by postoperative physical limitations and restrictions. Our objective was to assess the utility of neuromuscular electrical stimulation (NMES) as an adjunct to current rehabilitative care following postsurgical discharge and prior to entry into CR on indices of physical function in patients undergoing coronary artery bypass graft surgery. METHODS Patients were randomized to 4 wk of bilateral, NMES (5 d/wk) to their quadriceps muscles or no intervention (control). Physical function testing was performed at hospital discharge and 4 wk post-discharge using the Short Physical Performance Battery and the 6-min walk tests. Data from 37 patients (19 control/18 NMES) who completed the trial were analyzed. The trial was registered at ClinicalTrials.gov (NCT03892460). RESULTS Physical function measures improved from discharge to 4 wk post-surgery across our entire cohort (P < .001). Patients randomized to NMES, however, showed greater improvements in 6-min walk test distance and power output compared with controls (P < .01). CONCLUSION Our results provide evidence supporting the utility of NMES to accelerate recovery of physical function after coronary artery bypass graft surgery.

Obesity has become one of the most pressing public health issues of the 21st century and currently affects a substantial proportion of the older adult population. Although the cardiometabolic complications are well documented, research from the past 20 years has drawn attention to the detrimental effects of obesity on physical performance in older adults. Obesity-related declines in physical performance are due, in part, to compromised muscle strength and power. Recent evidence suggests there are a number of mechanisms potentially underlying reduced whole muscle function, including alterations in myofilament protein function and cellular contractile properties, and these may be related to morphological adaptations, such as shifts in fiber type composition and increased intramyocellular lipid content within skeletal muscle. To date, even less research has focused on how exercise and weight loss interventions for obese older adults affect these mechanisms. In light of this work, we provide an update on the current knowledge related to obesity and skeletal muscle contractile function and highlight a number of questions to address potential etiologic mechanisms as well as intervention strategies, which may help advance our understanding of how physical performance can be improved among obese older adults.

Doxorubicin (Dox) is a commonly used chemotherapeutic that can adversely affect skeletal muscle, including causing muscle atrophy. Dox is known to induce an event known as mitochondrial permeability transition (MPT) in cardiac muscle and this plays an important role in Dox-mediated cardiac toxicity. Further to this, recent evidence identifies MPT as a mechanism of atrophy in skeletal muscle, suggesting that MPT may underlie some of the Dox-related toxicity in skeletal muscle. To test this hypothesis, we used cultured human primary myotubes, C2C12 myotubes, and single adult mouse flexor digitorum brevis (FDB) muscle fibers in experiments involving Dox treatment with or without inhibitors of MPT. Dox treatment of myotubes caused myonuclear translocation of the mitochondrial protein apoptosis inducing factor (AIF) and increased mitochondrial reactive oxygen species (mROS), consistent with the known consequences of MPT. Furthermore, Dox caused atrophy in C2C12 myotubes grown on patterned plates, human primary myotubes, and single muscle fibers from adult mice. Notably, Dox-induced atrophy could be prevented by a wide variety of agents that inhibit MPT, as well as by inhibiting mROS or Caspase 3. In conclusion, our results indicate that MPT plays an important role in driving Dox-mediated skeletal muscle atrophy.

Macrophages are important mediators of skeletal muscle function in both healthy and diseased states. In vivo specific depletion of macrophages provides an experimental method to understand physiological and patho-physiological effects of macrophages. Systemic depletion of macrophages can deplete skeletal muscle macrophages but also alters systemic inflammatory responses and metabolism, which confounds the muscle specific effects of macrophage depletion. The primary aim of this manuscript is to evaluate two methods of murine intramuscular macrophage depletion in an acute lung injury-associated indirect skeletal muscle wasting mouse model. Adult C57BL/6 (WT) and Macrophage Fas-Induced Apoptosis (MaFIA, C57BL/6-Tg) mice received clodronate liposomes or the dimerization drug AP20187 through intramuscular injection of the tibialis anterior muscle compartment, respectively. Vehicle control was injected in the contralateral muscle. We demonstrate intramuscular AP20187 in the MaFIA mouse depletes macrophages but causes an infiltration of CD45 intermediate neutrophils. In contrast, intramuscular clodronate liposomes successfully depletes macrophages without an associated increase in CD45 intermediate cells. In conclusion, intramuscular clodronate is effective for selective depletion of muscle macrophages without eliciting acute inflammation seen with AP20187 in MaFIA mice. This technique is an important tool to study the functional roles of macrophages in skeletal muscle.

Background:Anterior cruciate ligament (ACL) injuries and reconstruction (ACLR) promote quadriceps muscle atrophy and weakness that can persist for years, suggesting the need for more effective rehabilitation programs. Whether neuromuscular electrical stimulation (NMES) can be used to prevent maladaptations in skeletal muscle size and function is unclear.Purpose:To examine whether early NMES use, started soon after an injury and maintained through 3 weeks after surgery, can preserve quadriceps muscle size and contractile function at the cellular (ie, fiber) level in the injured versus noninjured leg of patients undergoing ACLR.Study Design:Randomized controlled trial; Level of evidence, 1.Methods:Patients (n = 25; 12 men/13 women) with an acute, first-time ACL rupture were randomized to NMES (5 d/wk) or sham (simulated microcurrent electrical nerve stimulation; 5 d/wk) treatment to the quadriceps muscles of their injured leg. Bilateral biopsies of the vastus lateralis were performed 3 weeks after surgery to measure skeletal muscle fiber size and contractility. Quadriceps muscle size and strength were assessed 6 months after surgery.Results:A total of 21 patients (9 men/12 women) completed the trial. ACLR reduced single muscle fiber size and contractility across all fiber types ( P < .01 to P < .001) in the injured compared with noninjured leg 3 weeks after surgery. NMES reduced muscle fiber atrophy ( P < .01) through effects on fast-twitch myosin heavy chain (MHC) II fibers ( P < .01 to P < .001). NMES preserved contractility in slow-twitch MHC I fibers ( P < .01 to P < .001), increasing maximal contractile velocity ( P < .01) and preserving power output ( P < .01), but not in MHC II fibers. Differences in whole muscle strength between groups were not discerned 6 months after surgery.Conclusion:Early NMES use reduced skeletal muscle fiber atrophy in MHC II fibers and preserved contractility in MHC I fibers. These results provide seminal, cellular-level data demonstrating the utility of the early use of NMES to beneficially modify skeletal muscle maladaptations to ACLR.Clinical Relevance:Our results provide the first comprehensive, cellular-level evidence to show that the early use of NMES mitigates early skeletal muscle maladaptations to ACLR.Registration:NCT02945553 (ClinicalTrials.gov identifier)

Critical to digital medicine is the promise of improved patient monitoring to allow assessment and personalized intervention to occur in real-time. Wearable sensor-enabled observation of physiological data in free-living conditions is integral to this vision. However, few open-source algorithms have been developed for analyzing and interpreting these data which slows development and the realization of digital medicine. There is clear need for open-source tools that analyze free-living wearable sensor data and particularly for gait analysis, which provides important biomarkers in multiple clinical populations. We present an open-source analytical platform for automated free-living gait analysis and use it to investigate a novel, multi-domain (accelerometer and electromyography) asymmetry measure for quantifying rehabilitation progress in patients recovering from surgical reconstruction of the anterior cruciate ligament (ACL). Asymmetry indices extracted from 41,893 strides were more strongly correlated (r = −0.87, p r = 0.25, p = 0.52) and significantly differed between patients 2- and 17-weeks post-op (p p

INTRODUCTION: Older adults can experience periods of inactivity related to disease or illness, which can hasten the development of physical disability, in part, through reductions in skeletal muscle strength and power. To date no study has characterized adaptations in skeletal muscle physical function in response to reduced daily physical activity. METHODS: Participants (15 men, 69±2 years, 15 women, 68±4 years) restricted their daily steps (

Objective Resistance training (RT) can improve whole muscle strength without increasing muscle fiber size or contractility. Neural adaptations, which lead to greater neural activation of muscle, may mediate some of these improvements, particularly in older adults, where motor neuron denervation is common. The purpose of this study was to explore the relationship of neural adaptations, as reflected by neural cell adhesion molecule (NCAM) expression, to improvements in (1) whole muscle strength and (2) muscle fiber size following RT in older adults with knee osteoarthritis. We performed whole muscle strength measurements and immunohistochemical analysis of fiber size, type, and NCAM expression before and after a 14-week RT program. Results RT increased whole-muscle strength as measured by 1-repetition maximum (1-RM) leg press (P = 0.01), leg extension (P = 0.03), and knee extensor peak torque (P = 0.050), but did not alter NCAM expression. Greater NCAM expression in myosin heavy chain (MHC) II fibers was associated with greater whole muscle strength gains (knee extensor peak torque r = 0.93; P Trial registration NCT01190046

Increased adiposity is associated with reduced skeletal muscle function in older adults, but the mechanisms underlying this relationship remain unclear. To explore whether skeletal muscle properties track with adiposity, whole-muscle, cellular, and molecular function were examined in relation to adiposity measured at various anatomical levels in healthy older (60–80 years) men and women. Although women had greater absolute and relative body and thigh fat than men, quadriceps muscle attenuation, an index of intramuscular lipid content, was similar between sexes. At the whole-muscle level, greater quadriceps attenuation was associated with reduced knee extensor function in women, but not men. In women, decreased myosin heavy chain I and IIA fiber-specific force was associated with higher intramuscular lipid content, which may be explained, in part, by the reduced myofilament lattice stiffness found in myosin heavy chain IIA fibers. Longer myosin attachment times in myosin heavy chain I fibers from men and women were associated with greater amounts of adipose tissue, suggesting that fat deposits lead to slower myosin–actin cross-bridge kinetics. Our results indicate greater quantities of adipose tissue alter myofilament properties and cross-bridge kinetics, which may partially explain the adiposity-induced decrements in single-fiber and whole-muscle function of older adults, especially women.

How breast cancer and its treatments affect skeletal muscle is not well defined. To address this question, we assessed skeletal muscle structure and protein expression in 13 women who were diagnosed with breast cancer and receiving adjuvant chemotherapy following tumor resection and 12 nondiseased controls. Breast cancer patients showed reduced single-muscle fiber cross-sectional area and fractional content of subsarcolemmal and intermyofibrillar mitochondria. Drugs commonly used in breast cancer patients (doxorubicin and paclitaxel) caused reductions in myosin expression, mitochondrial loss, and increased reactive oxygen species (ROS) production in C2C12 murine myotube cell cultures, supporting a role for chemotherapeutics in the atrophic and mitochondrial phenotypes. Additionally, concurrent treatment of myotubes with the mitochondrial-targeted antioxidant MitoQ prevented chemotherapy-induced myosin depletion, mitochondrial loss, and ROS production. In patients, reduced mitochondrial content and size and increased expression and oxidation of peroxiredoxin 3, a mitochondrial peroxidase, were associated with reduced muscle fiber cross-sectional area. Our results suggest that chemotherapeutics may adversely affect skeletal muscle in patients and that these effects may be driven through effects of these drugs on mitochondrial content and/or ROS production.

Muscle may contribute to the systemic inflammatory environment during critical illness, but leukocyte interaction and cytokine influence on muscle and its response has not been fully explored in this context. Using an in vivo model of intratracheal lipopolysaccharide (IT LPS)-induced acute lung injury, we show that skeletal muscle rapidly responds with expression of proinflammatory genes, which may be explained by migration of LPS into the circulation. Treatment of mature C2C12 myotubes with LPS at a level achieved in the circulation following IT LPS elicited a proinflammatory cytokine expression profile similar to that of in vivo murine muscle following IT LPS. Stimulation with toll-like receptor (TLR) 2 and 3 agonists provoked comparable responses in C2C12 myotubes. Additionally, co-cultures of C2C12 myotubes and bone marrow-derived macrophages (BMDM) identified the capacity of macrophages to increase myotube proinflammatory gene expression, with tumor necrosis factor-α (TNFα) gene and protein expression largely attributable to BMDM. To investigate the contribution of TNFα in the synergy of the co-culture environment, C2C12 myotubes were treated with recombinant TNFα, co-cultures were established using TNF-deficient BMDM, and co-cultures were also depleted of TNFα using antibodies. To determine whether the in vitro observations were relevant in vivo, mice received intramuscular administration of LPS ± TNFα or TNFα-neutralizing antibodies and showed that TNFα is both sufficient and necessary to induce synergistic cytokine release from muscle. Taken together, these data demonstrate how skeletal muscle tissue may contribute proinflammatory cytokines following acute endotoxin injury and the potential of leukocytes to augment this response via TNFα secretion.

As studies examining the hypertrophic effects of resistance training (RT) at the cellular level have produced inconsistent results, we performed a systematic review and meta-analysis to investigate muscle fiber size before and after a structured RT intervention in older adults. A random-effects model was used to calculate mean effect size (ES) and 95% confidence intervals (CI). Thirty-five studies were included (age range: 59.0–88.5 yr), and 44 and 30 effects were used to estimate RT impact on myosin heavy chain (MHC) I and II fiber size. RT produced moderate-to-large increases in MHC I (ES = +0.51, 95%CI +0.31 to +0.71; P < 0.001) and II (ES = +0.81, 95%CI +0.56 to +1.05; P < 0.001) fiber size, with men and women having a similar response. Age was negatively associated with change in muscle fiber size for both fiber types (MHC I: R2 = 0.11, β = −0.33, P = 0.002; MHC II: R2 = 0.10, β = −0.32, P = 0.04), indicating a less robust hypertrophic response as age increases in older adults. Unexpectedly, a higher training intensity (defined as percentage of one-repetition maximum) was associated with a smaller increase in MHC II fiber size ( R2 = 15.09%, β = −0.39, P = 0.01). Notably, MHC II fiber subtypes (IIA, IIX, IIAX) were examined less frequently, but RT improved their size. Overall, our findings indicate that RT induces cellular hypertrophy in older adults, although the effect is attenuated with increasing age. In addition, hypertrophy of MHC II fibers was reduced with higher training intensity, which may suggest a failure of muscle fibers to hypertrophy in response to high loads in older adults.

Exercise has numerous benefits for patients with cancer, but implementation is challenging because of practical and logistical hurdles. This study examined whether neuromuscular electrical stimulation (NMES) can serve as a surrogate for classic exercise by eliciting an exercise training response in skeletal muscle of women diagnosed with breast cancer undergoing chemotherapy. Patients (n = 22) with histologically confirmed stage I, II, or III breast cancer scheduled to receive neoadjuvant or adjuvant chemotherapy were randomized to 8 wk of bilateral neuromuscular electrical stimulation (NMES; 5 days/wk) to their quadriceps muscles or control. Biopsy of the vastus lateralis was performed at baseline and after 8 wk of intervention to assess muscle fiber size, contractility, and mitochondrial content. Seventeen patients (8 control/9 NMES) completed the trial and were included in analyses. NMES promoted muscle fiber hypertrophy (P < 0.001), particularly in fast-twitch, myosin heavy chain (MHC) IIA fibers (P < 0.05) and tended to induce fiber type shifts in MHC II fibers. The effects of NMES on single-muscle fiber contractility were modest, and it was unable to prevent declines in the function in MHC IIA fibers. NMES did not alter intermyofibrillar mitochondrial content/structure but was associated with reductions in subsarcolemmal mitochondria. Our results demonstrate that NMES induces muscle fiber hypertrophy and fiber type shifts in MHC II fibers but had minimal effects on fiber contractility and promoted reductions in subsarcolemmal mitochondria. Further studies are warranted to evaluate the utility of NMES as an exercise surrogate in cancer patients and other conditions. NEW & NOTEWORTHY This is the first study to evaluate whether neuromuscular electrical stimulation (NMES) can be used as an exercise surrogate to improve skeletal muscle fiber size or function in cancer patients receiving treatment. We show that NMES promoted muscle fiber hypertrophy and fiber type shifts but had minimal effects on single-fiber contractility and reduced subsarcolemmal mitochondria.

Background Knee extensor muscle performance is reduced after lower extremity trauma and orthopedic surgical interventions. At-home use of neuromuscular electrical stimulation (NMES) may improve functional recovery, but adherence to at-home interventions is low. Greater benefits from NMES may be realized with closer monitoring of adherence to at-home prescriptions and more frequent patient-provider interactions. Objective This study aimed to develop a cyber-physical system to monitor at-home adherence to NMES prescription and facilitate patient-provider communications to improve adherence in near real time. Methods The RehabTracker cyber-physical system was developed to accomplish this goal and comprises four components: (1) hardware modifications to a commercially available NMES therapy device to monitor device use and provide Bluetooth functionality; (2) an iPhone Operating System–based mobile health (mHealth) app that enables patient-provider communications in near real time; (3) a clinician portal to allow oversight of patient adherence with device use; and (4) a back-end server to store data, enable adherence analysis, and send automated push notifications to the patient. These four elements were designed to be fully compliant with the Health Insurance Portability and Accountability Act. The system underwent formative testing in a cohort of patients following anterior cruciate ligament rupture (n=7) to begin to assess face validity. Results Compared with the NMES device software–tracked device use, the RehabTracker system recorded 83% (40/48) of the rehabilitation sessions, with 100% (32/32) of all sessions logged by the system in 4 out of 7 patients. In patients for whom tracking of automated push notifications was enabled, 100% (29/29) of the push notifications sent by the back-end server were received by the patient. Process, hardware, and software issues contributing to these inaccuracies are detailed. Conclusions RehabTracker represents a promising mHealth app for tracking and improving adherence with at-home NMES rehabilitation programs and warrants further refinement and testing.

PURPOSE: Cancer therapy diminishes strength and physical function in cancer survivors. Whether oncology rehabilitation (OR) exercise training following therapy can correct these deficits, and whether its effectiveness differs by age, is not clear. We examine the utility of a clinically based, 12-week, combined aerobic and resistance training intervention on muscle strength and physical function in two age groups of cancer survivors. METHODS: Strength and physical function measures were assessed in middle-aged (45 to 64 years) and older (≥ 65 years) patients following treatment for stage 0–III cancer before and after the OR training program. RESULTS: Older patients had lower physical function compared to middle-aged patients across a range of subjective and objective measures at baseline, and exercise improved all indices of physical function and strength in both age groups. Compared to the middle-aged individuals, older participants tended to have less improvement leg strength and the 5 time sit to stand (5TSTS) test as a result of OR. In models predicting post-intervention measures, older age contributed to less improvement in walking distance and power as well as the 5TSTS test. CONCLUSION: Prior to beginning the OR exercise program, middle-aged patients had higher physical function compared to older patients. However, a 12-week aerobic and resistance training intervention improved physical function across both age groups, although older age did limit responsiveness in some physical function measures. The physical function and strength of middle-aged and older cancer survivors improve in response to an exercise-based OR program after cancer treatment.

Skeletal muscle myosin heavy chain (MyHC) fiber type composition is a critical determinant of overall muscle function and health. Various approaches interrogate fiber type at the single cell, but the two most commonly utilized are single-muscle fiber sodium dodecyl sulfate-polyacrylamide gel electrophoresis (smfSDS-PAGE) and fluorescent immunohistochemistry (IHC). Although smfSDS-PAGE is generally considered the “gold standard,” IHC is more commonly used because of its time-effectiveness and relative ease. Unfortunately, there is lingering inconsistency on how best to accurately and quickly determine fiber type via IHC and an overall misunderstanding regarding pure fiber type proportions, specifically the abundance of fibers exclusively expressing highly glycolytic MyHC IIX in humans. We therefore 1) present information and data showing the low abundance of pure MyHC IIX muscle fibers in healthy human skeletal muscle and 2) leverage this information to provide straightforward protocols that are informed by human biology and employ inexpensive, easily attainable antibodies for the accurate determination of fiber type.

High-intensity resistance exercise (REX) training increases physical capacity, in part, by improving muscle cell size and function. Moderate-intensity REX, which is more feasible for many older adults with disease and/or disability, also increases physical function, but the mechanisms underlying such improvements are not understood. Therefore, we measured skeletal muscle structure and function from the molecular to the tissue level in response to 14 wk of moderate-intensity REX in physically inactive older adults with knee osteoarthritis ( n = 17; 70 ± 1 yr). Although REX training increased quadriceps muscle cross-sectional area (CSA), average single-fiber CSA was unchanged because of reciprocal changes in myosin heavy chain (MHC) I and IIA fibers. Intermyofibrillar mitochondrial content increased with training because of increases in mitochondrial size in men, but not women, with no changes in subsarcolemmal mitochondria in either sex. REX increased whole muscle contractile performance similarly in men and women. In contrast, adaptations in single-muscle fiber force production per CSA (i.e., tension) and contractile velocity varied between men and women in a fiber type-dependent manner, with adaptations being explained at the molecular level by differential changes in myosin-actin cross-bridge kinetics and mechanics and single-fiber MHC protein expression. Our results are notable compared with studies of high-intensity REX because they show that the effects of moderate-intensity REX in older adults on muscle fiber size/structure and myofilament function are absent or modest. Moreover, our data highlight unique sex-specific adaptations due to differential cellular and subcellular structural and functional changes.NEW & NOTEWORTHY Moderate-intensity resistance training causes sex-specific adaptations in skeletal muscle structure and function at the cellular and molecular levels in inactive older adult men and women with knee osteoarthritis. However, these responses were minimal compared with high-intensity resistance training. Thus adjuncts to moderate-intensity training need to be developed to correct underlying cellular and molecular structural and functional deficits that are at the root of impaired physical function in this mobility-limited population.

Summary Background & aims Cancer patients frequently experience weight loss, with negative consequences for functionality and prognosis. The extent to which muscle atrophy contributes to weight loss, however, is not clear, as few studies have directly measured muscle fiber morphology in cancer patients. Methods Whole body and regional tissue composition were measured, along with the cross-sectional area (CSA) and fiber type of mechanically-isolated, single muscle fibers, in 19 cancer patients (8 with a history of weight loss, 11 weight-stable) and 15 non-diseased controls. Results Whole body fat mass was reduced in cancer patients with a history of weight loss, but no differences in whole body or leg fat-free mass were apparent. In contrast, reductions (∼20%) in single muscle fiber CSA were found in both slow-twitch, myosin heavy chain (MHC) I and fast-twitch, MHC IIA fibers in both weight-stable patients and those with a history of weight loss. Fiber type distribution showed a shift towards a fast-twitch phenotype compared to controls, which may preserve muscle function in cancer patients despite atrophy, as positive relationships were found between the fractions of hybrid MHC IIAX and I/IIA fibers and 6-min walk performance. Conclusions Our results suggest that, although not apparent from whole body or regional measurements, cancer is associated with reduced skeletal muscle fiber size independent of weight loss history and a shift towards fast-twitch fibers, phenotypes that resemble adaptations to muscle disuse.

BACKGROUND Knee extensor muscle performance is reduced after lower extremity trauma and orthopedic surgical interventions. At-home use of neuromuscular electrical stimulation (NMES) may improve functional recovery, but adherence to at-home interventions is low. Greater benefits from NMES may be realized with closer monitoring of adherence to at-home prescriptions and more frequent patient-provider interactions. OBJECTIVE This study aimed to develop a cyber-physical system to monitor at-home adherence to NMES prescription and facilitate patient-provider communications to improve adherence in near real time. METHODS The RehabTracker cyber-physical system was developed to accomplish this goal and comprises four components: (1) hardware modifications to a commercially available NMES therapy device to monitor device use and provide Bluetooth functionality; (2) an iPhone Operating System–based mobile health (mHealth) app that enables patient-provider communications in near real time; (3) a clinician portal to allow oversight of patient adherence with device use; and (4) a back-end server to store data, enable adherence analysis, and send automated push notifications to the patient. These four elements were designed to be fully compliant with the Health Insurance Portability and Accountability Act. The system underwent formative testing in a cohort of patients following anterior cruciate ligament rupture (n=7) to begin to assess face validity. RESULTS Compared with the NMES device software–tracked device use, the RehabTracker system recorded 83% (40/48) of the rehabilitation sessions, with 100% (32/32) of all sessions logged by the system in 4 out of 7 patients. In patients for whom tracking of automated push notifications was enabled, 100% (29/29) of the push notifications sent by the back-end server were received by the patient. Process, hardware, and software issues contributing to these inaccuracies are detailed. CONCLUSIONS RehabTracker represents a promising mHealth app for tracking and improving adherence with at-home NMES rehabilitation programs and warrants further refinement and testing. CLINICALTRIAL

Muscle contraction may protect against the effects of chemotherapy to cause skeletal muscle atrophy, but the mechanisms underlying these benefits are unclear. To address this question, we utilized in vitro modeling of contraction and mechanotransduction in C2C12 myotubes treated with doxorubicin (DOX; 0.2 μM for 3 days). Myotubes expressed contractile proteins and organized these into functional myofilaments, as electrical field stimulation (STIM) induced intracellular calcium (Ca2+) transients and contractions, both of which were prevented by inhibition of membrane depolarization. DOX treatment reduced myotube myosin content, protein synthesis, and Akt (S308) and forkhead box O3a (FoxO3a; S253) phosphorylation and increased muscle RING finger 1 (MuRF1) expression. STIM (1 h/day) prevented DOX-induced reductions in myotube myosin content and Akt and FoxO3a phosphorylation, as well as increases in MuRF1 expression, but did not prevent DOX-induced reductions in protein synthesis. Inhibition of myosin-actin interaction during STIM prevented contraction and the antiatrophic effects of STIM without affecting Ca2+ cycling, suggesting that the beneficial effect of STIM derives from mechanotransductive pathways. Further supporting this conclusion, mechanical stretch of myotubes recapitulated the effects of STIM to prevent DOX suppression of FoxO3a phosphorylation and upregulation of MuRF1. DOX also increased reactive oxygen species (ROS) production, which led to a decrease in mitochondrial content. Although STIM did not alter DOX-induced ROS production, peroxisome proliferator-activated receptor-γ coactivator-1α and antioxidant enzyme expression were upregulated, and mitochondrial loss was prevented. Our results suggest that the activation of mechanotransductive pathways that downregulate proteolysis and preserve mitochondrial content protects against the atrophic effects of chemotherapeutics.

This paper presents an automated, wearable sensor-based remote gait analysis method and demonstrates its utility by evaluating gait in patients recovering from anterior cruciate ligament (ACL) reconstruction. Patients wore a single wearable sensor over the rectus femoris of each leg to collect over 15 hours of 3-axis accelerometer and surface electromyography data during daily life. A support vector machine classifier was used to identify four second windows of walking activity. Across all subjects 10,451 strides were extracted from these windows and categorized as occurring during either fast or slow walking. Muscle activation and 3-axis thigh acceleration time-series for each stride were resampled as a percentage of stride cycle and ensemble curves from both legs were compared using correlation as an index of gait pattern symmetry. Our results suggest the proposed method successfully identifies time-series gait asymmetries between affected and unaffected legs when comparing patients early post-surgery ( $ weeks) and later ( $> \pmb {14}$ weeks) in recovery for each walking speed. These results point toward future use of this approach as a digital biomarker for rehabilitation progress in this population.

Introduction Statins have well-known benefits on cardiovascular mortality, though up to 15% of patients experience side effects. With guidelines from the American Heart Association, American College of Cardiology, and American Diabetes Association expected to double the number of statin users, the overall incidence of myalgia and myopathy will increase. Methods We evaluated skeletal muscle structure and contractile function at the molecular, cellular, and whole tissue levels in 12 statin tolerant and 12 control subjects. Results Myosin isoform expression, fiber type distributions, single fiber maximal Ca2+-activated tension, and whole muscle contractile force were similar between groups. No differences were observed in myosin-actin cross-bridge kinetics in myosin heavy chain I or IIA fibers. Conclusions We found no evidence for statin-induced changes in muscle morphology at the molecular, cellular, or whole tissue levels. Collectively, our data show that chronic statin therapy in healthy asymptomatic individuals does not promote deleterious myofilament structural or functional adaptations. Muscle Nerve 53: 242–251, 2016

We examine leg motion and quadriceps muscle activation patterns during free-living activity in a cross-sectional sample of patients recovering from anterior cruciate ligament (ACL) reconstruction using wearable sensors. Analysis suggests that this technology is feasible, and captures expected differences in daily muscle activity between the affected and contralateral limbs within and across patients and, during gait, differences in muscle activation patterns and kinematics across patients associated with recovery progress. Results point toward the need for future studies to explore these indicators of rehabilitation progress longitudinally in patients recovering from ACL reconstruction.

The pathophysiology of cancer cachexia remains complex. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and the Google search engine. In this review, we focus on the different mediators of impaired anabolism and upregulated catabolism that alter the skeletal muscle homeostasis resulting in the wasting of cancer cachexia. We present recent evidence of targeted treatment modalities from clinical trials along with their potential mechanisms of action. We also report on the most current evidence from randomized clinical trials using multimodal treatments in patients with cancer cachexia, but also the evidence from head and neck cancer-specific trials. A more complete understanding of the pathophysiology of the syndrome may lead to more effective targeted therapies and improved outcomes for patients.

Skeletal muscle contractile performance is governed by the properties of its constituent fibers, which are, in turn, determined by the molecular interactions of the myofilament proteins. To define the molecular determinants of contractile function in humans, we measured myofilament mechanics during maximal Ca2+-activated and passive isometric conditions in single muscle fibers with homogenous (I and IIA) and mixed (I/IIA and IIA/X) myosin heavy chain (MHC) isoforms from healthy, young adult male ( n = 5) and female ( n = 7) volunteers. Fibers containing only MHC II isoforms (IIA and IIA/X) produced higher maximal Ca2+-activated forces over the range of cross-sectional areas (CSAs) examined than MHC I fibers, resulting in higher (24–42%) specific forces. The number and/or stiffness of the strongly bound myosin-actin cross bridges increased in the higher force-producing MHC II isoforms and, in all isoforms, better predicted force than CSA. In men and women, cross-bridge kinetics, in terms of myosin attachment time and rate of myosin force production, were independent of CSA, although women had faster (7–15%) kinetics. The relative proportion of cross bridges and/or their stiffness was reduced as fiber size increased, causing a decline in specific force. Results from our examination of molecular mechanisms across the range of physiological CSAs explain the variation in specific force among the different fiber types in human skeletal muscle, which may have relevance to understanding how various physiological and pathophysiological conditions modulate single-fiber and whole muscle contractility.

Purpose The value of exercise and rehabilitative interventions for cancer survivors is increasingly clear, and oncology rehabilitation programs could provide these important interventions. However, a pathway to create oncology rehabilitation has not been delineated. Community-based cardiac rehabilitation (CR) programs staffed by health care professionals with experience in providing rehabilitation and secondary prevention services to individuals with coronary heart disease are widely available and provide a potential model and location for oncology rehabilitation programs. Our purpose was to outline the rehabilitative needs of cancer survivors and demonstrate how oncology rehabilitation can be created using a CR model. Methods We identify the impairments associated with cancer and its therapy that respond to rehabilitative interventions. Components of the CR model that would benefit cancer survivors are described. An example of an oncology rehabilitation program using a CR model is presented. Results Cancer survivors have impairments associated with cancer and its therapy that improve with rehabilitation. Our experience demonstrates that effective rehabilitation services can be provided utilizing an existing CR infrastructure. Few adjustments to current CR models would be needed to provide oncology rehabilitation. Preliminary evidence suggests that cancer survivors participating in an oncology rehabilitation program experience improvements in psychological and physiologic parameters. Conclusions Utilizing the CR model of rehabilitative services and disease management provides a much needed mechanism to bring oncology rehabilitation to larger numbers of cancer survivors.

It is difficult for crane operators to lift and maneuver payloads without causing significant, uncontrolled motion. Consequently, research in the area of crane operation has focused on designing controllers to minimize payload swing. However, lifting long and slender payloads (e.g., steel I-beams) from a non-level surface (e.g., like many outdoor construction sites) has not been addressed in much detail. This paper evaluates the amplitude of residual swing and robustness of two different control methodologies while hoisting a slender payload up into the air from an inclined surface. A semi-automatic approach, where the crane operator controls the lift direction and a proportional-integral-derivative (PID) controller adjusts the overhead trolley position, was developed. Experimental tests demonstrate that this method reduces the peak amplitude of residual vibration by about 80% for most non-zero incline angles.

A variety of therapeutic and/or diagnostic nanoparticles (NPs), or nanomedicines, have been formulated for improved drug delivery and imaging applications. Microfluidic technology enables continuous and highly reproducible synthesis of NPs through controlled mixing processes at the micro- and nanoscale. Yet, the inherent low-throughput remains a critical roadblock, precluding the probable applications of new nanomedicines for clinical translation. Here we present robust manufacturing of lipid-polymer NPs (LPNPs) through feedback controlled operation of parallelized swirling microvortex reactors (SMRs). We demonstrate the capability of a single SMR to continuously produce multicomponent NPs and the high-throughput performance of parallelized SMRs for large-scale production (1.8 kg d-1) of LPNPs while maintaining the physicochemical properties. Finally, we present robust and reliable manufacturing of NPs by integrating the parallelized SMR platform with our custom high-precision feedback control system that addresses unpredictable disturbances during the production. Our approach may contribute to efficient development and optimization of a wide range of multicomponent NPs for medical imaging and drug delivery, ultimately facilitating good manufacturing practice (GMP) production and accelerating the clinical translation.

Fatigue is a common symptom of numerous acute and chronic diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, multiple sclerosis, heart failure, cancer, and many others. In these multi-system diseases the physiological determinants of enhanced fatigue encompass a combination of metabolic, neurological, and myofibrillar adaptations. Previous research studies have focused on adaptations specific to skeletal muscle and their role in fatigue. However, most have neglected the contribution of physical inactivity in assessing disease syndromes, which, through deconditioning, likely contributes to symptomatic fatigue. In this commentary, we briefly review disease-related muscle phenotypes in the context of whether they relate to the primary disease or whether they develop secondary to reduced physical activity. Knowledge of the etiology of the skeletal muscle adaptations in these conditions and their contribution to fatigue symptoms is important for understanding the utility of exercise rehabilitation as an intervention to alleviate the physiological precipitants of fatigue.

Physical inactivity that accompanies ageing and disease may hasten disability by reducing skeletal muscle contractility. To characterize skeletal muscle functional adaptations to muscle disuse, we compared contractile performance at the molecular, cellular and whole‐muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced‐stage, symptomatic knee osteoarthritis (OA) (n = 16). OA patients showed reduced (P < 0.01) knee extensor function. At the cellular level, single muscle fibre force production was reduced in OA patients in myosin heavy chain (MHC) I and IIA fibres (both P < 0.05) and differences in IIA fibres persisted after adjustments for fibre cross‐sectional area (P < 0.05). Although no group differences in contractile velocity or power output were found for any fibre type, sex was found to modify the effect of OA, with a reduction in MHC IIA power output and a trend towards reduced shortening velocity in women, but increases in both variables in men (P < 0.05 and P = 0.07, respectively). At the molecular level, these adaptations in MHC IIA fibre function were explained by sex‐specific differences (P ≤ 0.05) in myosin–actin cross‐bridge kinetics. Additionally, cross‐bridge kinetics were slowed in MHC I fibres in OA patients (P < 0.01), attributable entirely to reductions in women with knee OA (P < 0.05), a phenotype that could be reproduced in vitro by chemical modification of protein thiol residues. Our results identify molecular and cellular functional adaptations in skeletal muscle that may contribute to reduced physical function with knee OA‐associated muscle disuse, with sex‐specific differences that may explain a greater disposition towards disability in women.

Cachexia is a profoundly debilitating wasting syndrome that affects patients with head and neck cancer and often contributes to their demise. A comprehensive literature search was performed up to April 2013 using PubMed, the Cochrane Library, CINAHL, and the Google search engine. For the meta-analyses, pooled prevalence estimates were calculated with a confidence interval of 95% (95% CI) by using random effects modeling. In this review, we outlined the unique challenges of cancer cachexia among patients with head and neck cancer by reviewing its impacts on quality of life (QOL), morbidity, and mortality. We explored the prevalence of different clinical markers of cachexia at the time of diagnosis and before and after treatment. Finally, we present updates regarding the diagnosis of cancer cachexia and recent findings, such as cardiac dysfunction that warrant clinical attention to more carefully identify patients at risk and potentially lead to better outcomes.

We hypothesize that age-related skeletal muscle dysfunction and physical disability may be partially explained by alterations in the function of the myosin molecule. To test this hypothesis, skeletal muscle function at the whole muscle, single fiber, and molecular levels was measured in young (21–35 yr) and older (65–75 yr) male and female volunteers with similar physical activity levels. After adjusting for muscle size, older adults had similar knee extensor isometric torque values compared with young, but had lower isokinetic power, most notably in women. At the single-fiber and molecular levels, aging was associated with increased isometric tension, slowed myosin actin cross-bridge kinetics (longer myosin attachment times and reduced rates of myosin force production), greater myofilament lattice stiffness, and reduced phosphorylation of the fast myosin regulatory light chain; however, the age effect was driven primarily by women (i.e., age-by-sex interaction effects). In myosin heavy chain IIA fibers, single-fiber isometric tension and molecular level mechanical and kinetic indexes were correlated with whole muscle isokinetic power output. Collectively, considering that contractile dysfunction scales up through various anatomical levels, our results suggest a potential sex-specific molecular mechanism, reduced cross-bridge kinetics, contributes to the reduced physical capacity with aging in women. Thus these results support our hypothesis that age-related alterations in the myosin molecule contribute to skeletal muscle dysfunction and physical disability and indicate that this effect is stronger in women.

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(iω/ϕ)k, where E = a generalized viscoelastic stiffness; i = (−1)1/2; ω = angular frequency; ϕ = 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 complex modulus based on the hypothesis that the viscoelastic response arises from many intermittent molecular crosslinks, whose lifetimes longer than a critical threshold lifetime, tcrit, are distributed with an inverse power law proportional to t-(k+2). We demonstrate that E is proportional to the number and stiffness of crosslinks formed at any moment; the scaling factor ϕ is equivalent to reciprocal of tcrit; and the relative mean lifetime of the attached crosslinks is inversely proportional to the parameter k. To test whether electrostatic molecular bonds could be responsible for the fractional derivative viscoelasticity, we used chemically skinned human skeletal muscle as a one-dimensional model of a soft glassy substance. A reduction in ionic strength from 175 to 110 mEq resulted in a larger E with no change in k, consistent with a higher probability of interfilament molecular interactions. Thick to thin filament spacing was reduced by applying 4% w/v of the osmolyte Dextran T500, which also resulted in a larger E, indicating a greater probability of crosslink formation in proportion to proximity. A 10°C increase in temperature resulted in an increase in k, which corresponded to a decrease in cross-bridge attachment lifetime expected with higher temperatures. These theoretical and experimental results suggest that the fractional derivative viscoelasticity observed in some biological tissue arises as a mechanical consequence of electrostatic interactions, whose longest lifetimes are distributed with an inverse power law.