Differentially co-expressed myofibre transcripts associated with abnormal myofibre proportion in chronic obstructive pulmonary disease.

BACKGROUND: Skeletal muscle dysfunction is a common extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD). Alterations in skeletal muscle myosin heavy chain expression, with reduced type I and increased type II myosin heavy chain expression, are associated with COPD severity when studied in largely male cohorts. The objectives of this study were (1) to define an abnormal myofibre proportion phenotype in both males and females with COPD and (2) to identify transcripts and transcriptional networks associated with abnormal myofibre proportion in COPD. METHODS: Forty-six participants with COPD were assessed for body composition, strength, endurance and pulmonary function. Skeletal muscle biopsies from the vastus lateralis were assayed for fibre-type distribution and cross-sectional area via immunofluorescence microscopy and RNA-sequenced to generate transcriptome-wide gene expression data. Sex-stratified k-means clustering of type I and IIx/IIax fibre proportions was used to define abnormal myofibre proportion in participants with COPD and contrasted with previously defined criteria. Single transcripts and weighted co-expression network analysis modules were tested for correlation with the abnormal myofibre proportion phenotype. RESULTS: Abnormal myofibre proportion was defined in males with COPD (n = 29) as <18% type I and/or >22% type IIx/IIax fibres and in females with COPD (n = 17) as <36% type I and/or >12% type IIx/IIax fibres. Half of the participants with COPD were classified as having an abnormal myofibre proportion. Participants with COPD and an abnormal myofibre proportion had lower median handgrip strength (26.1 vs. 34.0 kg, P = 0.022), 6-min walk distance (300 vs. 353 m, P = 0.039) and forced expiratory volume in 1 s-to-forced vital capacity ratio (0.42 vs. 0.48, P = 0.041) compared with participants with COPD and normal myofibre proportions. Twenty-nine transcripts were associated with abnormal myofibre proportions in participants with COPD, with the upregulated NEB, TPM1 and TPM2 genes having the largest fold differences. Co-expression network analysis revealed that two transcript modules were significantly positively associated with the presence of abnormal myofibre proportions. One of these co-expression modules contained genes classically associated with muscle atrophy, as well as transcripts associated with both type I and type II myofibres, and was enriched for genetic loci associated with bone mineral density. CONCLUSIONS: Our findings indicate that there are significant transcriptional alterations associated with abnormal myofibre proportions in participants with COPD. Transcripts canonically associated with both type I and type IIa fibres were enriched in a co-expression network associated with abnormal myofibre proportion, suggesting altered transcriptional regulation across multiple fibre types.

Muscle Inflammation Susceptibility: A Potential Phenotype for Guiding Precision Rehabilitation After Total Hip Arthroplasty in End-Stage Osteoarthritis.

The progression of osteoarthritis of the hip to its end stage and ultimately to total hip arthroplasty (THA) is complex; the multifactorial pathophysiology involves myriad collaborating tissues in and around the diseased joint. We have named the heightened state of periarticular muscle inflammation at the time of surgery "muscle inflammation susceptibility" (MuIS) because it is distinct from systemic inflammation. In this review article, we discuss how MuIS and heightened atrophy-associated signaling in the periarticular skeletal muscles may contribute to reduced muscle mass, impaired muscle quality (ie, through fibrosis), and a muscle microenvironment that challenges regenerative capacity and thus functional recovery from THA. We also review directions for future research that should advance understanding of the key determinants of precision for optimized success of THA for each individual.

Perioperative assessment of muscle inflammation susceptibility in patients with end-stage osteoarthritis.

Many individuals with end-stage osteoarthritis (OA) undergo elective total hip/knee arthroplasty (THA/TKA) to relieve pain, improve mobility and quality of life. However, ∼30% suffer long-term mobility impairment following surgery. This may be in part due to muscle inflammation susceptibility (MuIS+), an overt proinflammatory pathology localized to skeletal muscle surrounding the diseased joint, present in some patients with TKA/THA. We interrogated the hypothesis that MuIS+ status results in a perturbed perioperative gene expression profile and decreases skeletal muscle integrity in patients with end-stage OA. Samples were leveraged from the two-site, randomized, controlled trial R01HD084124, NCT02628795. Participants were dichotomized based on surgical (SX) muscle gene expression of TNFRSF1A (TNF-αR). MuIS+/- samples were probed for gene expression and fibrosis. Paired and independent two-tailed t tests were used to determine differences between contralateral (CTRL) and surgical (SX) limbs and between-subject comparisons, respectively. Significance was declared at P < 0.05. Seventy participants (26M/44F; mean age 62.41 ± 8.86 yr; mean body mass index 31.10 ± 4.91 kg/m2) undergoing THA/TKA were clustered as MuIS+ (n = 24) or MuIS- (n = 46). Lower skeletal muscle integrity (greater fibrosis) exists on the SX versus CTRL limb (P < 0.001). Furthermore, MuIS+ versus MuIS- muscle exhibited higher proinflammatory (IL-6R and TNF-α) and catabolic (TRIM63) gene expression (P < 0.001, P = 0.004, and 0.024 respectively), with a trend for greater fibrosis (P = 0.087). Patients with MuIS+ exhibit more inflammation and catabolic gene expression in skeletal muscle of the SX limb, accompanied by decreased skeletal muscle integrity (Trend). This highlights the impact of MuIS+ status emphasizing the potential value of perioperative MuIS assessment to inform optimal postsurgical care.NEW & NOTEWORTHY This study assessed the skeletal muscle molecular characteristics associated with end-stage osteoarthritis and refined an important phenotype, in some patients, termed muscle inflammation susceptibility (MuIS+) that may be an important consideration following surgery. Furthermore, we provide evidence of differential inflammatory and catabolic gene expression between the contralateral and surgical limbs along with differences between the skeletal muscle surrounding the diseased hip versus knee joints.

A muscle cell-macrophage axis involving matrix metalloproteinase 14 facilitates extracellular matrix remodeling with mechanical loading.

The extracellular matrix (ECM) in skeletal muscle plays an integral role in tissue development, structural support, and force transmission. For successful adaptation to mechanical loading, remodeling processes must occur. In a large cohort of older adults, transcriptomics revealed that genes involved in ECM remodeling, including matrix metalloproteinase 14 (MMP14), were the most upregulated following 14 weeks of progressive resistance exercise training (PRT). Using single-cell RNA-seq, we identified macrophages as a source of Mmp14 in muscle following a hypertrophic exercise stimulus in mice. In vitro contractile activity in myotubes revealed that the gene encoding cytokine leukemia inhibitory factor (LIF) is robustly upregulated and can stimulate Mmp14 expression in macrophages. Functional experiments confirmed that modulation of this muscle cell-macrophage axis facilitated Type I collagen turnover. Finally, changes in LIF expression were significantly correlated with MMP14 expression in humans following 14 weeks of PRT. Our experiments reveal a mechanism whereby muscle fibers influence macrophage behavior to promote ECM remodeling in response to mechanical loading.

Skeletal muscle transcriptome response to a bout of endurance exercise in physically active and sedentary older adults.

Age-related declines in cardiorespiratory fitness and physical function are mitigated by regular endurance exercise in older adults. This may be due, in part, to changes in the transcriptional program of skeletal muscle following repeated bouts of exercise. However, the impact of chronic exercise training on the transcriptional response to an acute bout of endurance exercise has not been clearly determined. Here, we characterized baseline differences in muscle transcriptome and exercise-induced response in older adults who were active/endurance trained or sedentary. RNA-sequencing was performed on vastus lateralis biopsy specimens obtained before, immediately after, and 3 h following a bout of endurance exercise (40 min of cycling at 60%-70% of heart rate reserve). Using a recently developed bioinformatics approach, we found that transcript signatures related to type I myofibers, mitochondria, and endothelial cells were higher in active/endurance-trained adults and were associated with key phenotypic features including V̇o2peak, ATPmax, and muscle fiber proportion. Immune cell signatures were elevated in the sedentary group and linked to visceral and intermuscular adipose tissue mass. Following acute exercise, we observed distinct temporal transcriptional signatures that were largely similar among groups. Enrichment analysis revealed catabolic processes were uniquely enriched in the sedentary group at the 3-h postexercise timepoint. In summary, this study revealed key transcriptional signatures that distinguished active and sedentary adults, which were associated with difference in oxidative capacity and depot-specific adiposity. The acute response signatures were consistent with beneficial effects of endurance exercise to improve muscle health in older adults irrespective of exercise history and adiposity.NEW & NOTEWORTHY Muscle transcript signatures associated with oxidative capacity and immune cells underlie important phenotypic and clinical characteristics of older adults who are endurance trained or sedentary. Despite divergent phenotypes, the temporal transcriptional signatures in response to an acute bout of endurance exercise were largely similar among groups. These data provide new insight into the transcriptional programs of aging muscle and the beneficial effects of endurance exercise to promote healthy aging in older adults.

A 50 kdyne contusion spinal cord injury with or without the drug SS-31 was not associated with major changes in muscle mass or gene expression 14 d after injury in young male mice.

Spinal cord injury (SCI) leads to rapid muscle atrophy due to paralysis/paresis and subsequent disuse. SS-31 is a mitochondrial-targeting peptide that has shown efficacy in protecting skeletal muscle mass and function in non-SCI models of muscle wasting. We aimed to determine if SS-31 could prevent muscle loss after SCI. Male C57BL/6 mice aged 9 weeks underwent sham surgery or 50 kdyne contusion SCI and were administered daily injections of vehicle or 5 mg/kg SS-31 for 14 d. Both SCI groups had sustained losses in body mass compared to Sham animals and ~10% reductions in gastrocnemius, plantaris and tibialis anterior muscle mass after SCI with no clear effect of SS-31. Measurements of protein synthesis in the soleus and plantaris were similar among all groups. mRNA expression of atrophy-associated proinflammatory cytokines was also similar among all groups. There was elevation in MYH7 mRNA and a statistical reduction in MYH2 mRNA expression in the SCI+SS-31 animals compared to Sham animals. There was an SCI-induced reduction in mRNA expression of the E3 ligase FBXO32 (MAFbx), but no effect of SS-31. In summary, a 50 kdyne contusion SCI was able to reduce body mass but was not associated with substantial muscle atrophy or alterations in gene expression profiles associated with muscle health and function 14 d post-injury. SS-31 was not associated with protection against SCI-related changes in body or muscle mass, protein synthesis or gene expression in hindlimb muscles.

Muscle Fn14 gene expression is associated with fat-free mass retention during energy deficit at high altitude.

Intramuscular factors that modulate fat-free mass (FFM) loss in lowlanders exposed to energy deficit during high-altitude (HA) sojourns remain unclear. Muscle inflammation may contribute to FFM loss at HA by inducing atrophy and inhibiting myogenesis via the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible protein 14 (Fn14). To explore whether muscle inflammation modulates FFM loss reportedly developing during HA sojourns, muscle inflammation, myogenesis, and proteolysis were assessed in 16 men at sea level (SL) and following 21 days of energy deficit (-1862 ± 525 kcal/days) at high altitude (HA, 4300 m). Total body mass (TBM), FFM, and fat mass (FM) were assessed using DEXA. Gene expression and proteolytic enzymatic activities were assessed in muscle samples collected at rest at SL and HA. Participants lost 7.2 ± 1.8 kg TBM (P < 0.05); 43 ± 30% and 57 ± 30% of the TBM lost was FFM and FM, respectively. Fn14, TWEAK, TNF alpha-receptor (TNFα-R), TNFα, MYOGENIN, and paired box protein-7 (PAX7) were upregulated (P < 0.05) at HA compared to SL. Stepwise linear regression identified that Fn14 explained the highest percentage of variance in FFM loss (r2  = 0.511, P < 0.05). Dichotomization of volunteers into HIGH and LOW Fn14 gene expression indicated HIGH lost less FFM and more FM (28 ± 28% and 72 ± 28%, respectively) as a proportion of TBM loss than LOW (58 ± 26% and 42 ± 26%; P < 0.05) at HA. MYOGENIN gene expression was also greater for HIGH versus LOW (P < 0.05). These data suggest that heightened Fn14 gene expression is not catabolic and may protect FFM during HA sojourns.

Composition and richness of the serum microbiome differ by age and link to systemic inflammation.

Advanced age has been associated with alterations to the microbiome within the intestinal tract as well as intestinal permeability (i.e., "leaky gut"). Prior studies suggest that intestinal permeability may contribute to increases in systemic inflammation-an aging hallmark-possibly via microorganisms entering the circulation. Yet, no studies exist describing the state of the circulating microbiome among older persons. To compare microbiota profiles in serum between healthy young (20-35 years, n = 24) and older adults (60-75 years, n = 24) as well as associations between differential microbial populations and prominent indices of age-related inflammation. Unweighted Unifrac analysis, a measure of ß-diversity, revealed that microbial communities clustered differently between young and older adults. Several measures of α-diversity, including chao1 (p = 0.001), observed species (p = 0.001), and phylogenetic diversity (p = 0.002) differed between young and older adults. After correction for false discovery rate (FDR), age groups differed (all p values ≤ 0.016) in the relative abundance of the phyla Bacteroidetes, SR1, Spirochaetes, Bacteria_Other, TM7, and Tenericutes. Significant positive correlations (p values ≤ 0.017 after FDR correction) were observed between IGF1 and Bacteroidetes (ρ = 0.380), Spirochaetes (ρ = 0.528), SR1 (ρ = 0.410), and TM7 (ρ = 0.399). Significant inverse correlations were observed for IL6 with Bacteroidetes (ρ = - 0.398) and TM7 (ρ = - 0.423), as well as for TNFα with Bacteroidetes (ρ = - 0.344). Similar findings were observed at the class taxon. These data are the first to demonstrate that the richness and composition of the serum microbiome differ between young and older adults and that these factors are linked to indices of age-related inflammation.

Quantification and characterization of grouped type I myofibers in human aging.

INTRODUCTION: Myofiber type grouping is a histological hallmark of age-related motor unit remodeling. Despite the accepted concept that denervation-reinnervation events lead to myofiber type grouping, the completeness of those conversions remains unknown. METHODS: Type I myofiber grouping was assessed in vastus lateralis biopsies from Young (26 ± 4 years; n = 27) and Older (66 ± 4 years; n = 91) adults. Grouped and ungrouped type I myofibers were evaluated for phenotypic differences. RESULTS: Higher type I grouping in Older versus Young was driven by more myofibers per group (i.e., larger group size) (P < 0.05). In Older only, grouped type I myofibers displayed larger cross-sectional area, more myonuclei, lower capillary supply, and more sarco(endo)plasmic reticulum calcium ATPase I (SERCA I) expression (P < 0.05) than ungrouped type I myofibers. DISCUSSION: Grouped type I myofibers retain type II characteristics suggesting that conversion during denervation-reinnervation events is either progressive or incomplete. Muscle Nerve 57: E52-E59, 2018.

Weight management and physical activity throughout the cancer care continuum.

Mounting evidence suggests that weight management and physical activity (PA) improve overall health and well being, and reduce the risk of morbidity and mortality among cancer survivors. Although many opportunities exist to include weight management and PA in routine cancer care, several barriers remain. This review summarizes key topics addressed in a recent National Academies of Science, Engineering, and Medicine workshop entitled, "Incorporating Weight Management and Physical Activity Throughout the Cancer Care Continuum." Discussions related to body weight and PA among cancer survivors included: 1) current knowledge and gaps related to health outcomes; 2) effective intervention approaches; 3) addressing the needs of diverse populations of cancer survivors; 4) opportunities and challenges of workforce, care coordination, and technologies for program implementation; 5) models of care; and 6) program coverage. While more discoveries are still needed for the provision of optimal weight-management and PA programs for cancer survivors, obesity and inactivity currently jeopardize their overall health and quality of life. Actionable future directions are presented for research; practice and policy changes required to assure the availability of effective, affordable, and feasible weight management; and PA services for all cancer survivors as a part of their routine cancer care. CA Cancer J Clin 2018;68:64-89. © 2017 American Cancer Society.

OPN-a induces muscle inflammation by increasing recruitment and activation of pro-inflammatory macrophages.

NEW FINDINGS: What is the central question of this study? What is the functional relevance of OPN isoform expression in muscle pathology? What is the main finding and its importance? The full-length human OPN-a isoform is the most pro-inflammatory isoform in the muscle microenvironment, acting on macrophages and myoblasts in an RGD-integrin-dependent manner. OPN-a upregulates expression of tenascin-C (TNC), a known Toll-like receptor 4 (TLR4) agonist. Blocking TLR4 signalling inhibits the pro-inflammatory effects of OPN-a, suggesting that a potential mechanism of OPN action is by promoting TNC-TLR4 signalling. Although osteopontin (OPN) is an important mediator of muscle remodelling in health and disease, functional differences in human spliced OPN variants in the muscle microenvironment have not been characterized. We thus sought to define the pro-inflammatory activities of human OPN isoforms (OPN-a, OPN-b and OPN-c) on cells present in regenerating muscle. OPN transcripts were quantified in normal and dystrophic human and dog muscle. Human macrophages and myoblasts were stimulated with recombinant human OPN protein isoforms, and cytokine mRNA and protein induction was assayed. OPN isoforms were greatly increased in dystrophic human (OPN-a > OPN-b > OPN-c) and dog muscle (OPN-a = OPN-c). In healthy human muscle, mechanical loading also upregulated OPN-a expression (eightfold; P < 0.01), but did not significantly upregulate OPN-c expression (twofold; P > 0.05). In vitro, OPN-a displayed the most pronounced pro-inflammatory activity among isoforms, acting on both macrophages and myoblasts. In vitro and in vivo data revealed that OPN-a upregulated tenascin-C (TNC), a known Toll-like receptor 4 (TLR4) agonist. Inhibition of TLR4 signalling attenuated OPN-mediated macrophage cytokine production. In summary, OPN-a is the most abundant and functionally active human spliced isoform in the skeletal muscle microenvironment. Here, OPN-a promotes pro-inflammatory signalling in both macrophages and myoblasts, possibly through induction of TNC-TLR4 signalling. Together, our findings suggest that specific targeting of OPN-a and/or TNC signalling in the damaged muscle microenvironment may be of therapeutic relevance.

Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury.

Individuals with long-standing spinal cord injury (SCI) often present with extreme muscle atrophy and impaired glucose metabolism at both the skeletal muscle and whole body level. Persistent inflammation and increased levels of proinflammatory cytokines in the skeletal muscle are potential contributors to dysregulation of glucose metabolism and atrophy; however, to date no study has assessed the effects of long-standing SCI on their expression or intracellular signaling in the paralyzed muscle. In the present study, we assessed the expression of genes (TNFαR, TNFα, IL-6R, IL-6, TWEAK, TWEAK R, atrogin-1, and MuRF1) and abundance of intracellular signaling proteins (TWEAK, TWEAK R, NF-κB, and p-p65/p-50/105) that are known to mediate inflammation and atrophy in skeletal muscle. In addition, based on the effects of muscle inflammation on promotion of skeletal muscle fibrosis, we assessed the degree of fibrosis between myofibers and fascicles in both groups. For further insight into the distribution and variability of muscle fiber size, we also analyzed the frequency distribution of SCI fiber size. Resting vastus lateralis (VL) muscle biopsy samples were taken from 11 men with long-standing SCI (≈22 yr) and compared with VL samples from 11 able-bodied men of similar age. Our results demonstrated that chronic SCI muscle has heightened TNFαR and TWEAK R gene expression and NF-κB signaling (higher TWEAK R and phospho-NF-κB p65) and fibrosis, along with substantial myofiber size heterogeneity, compared with able-bodied individuals. Our data suggest that the TWEAK/TWEAK R/NF-κB signaling pathway may be an important mediator of chronic inflammation and fibrotic adaptation in SCI muscle.

Ribosome biogenesis may augment resistance training-induced myofiber hypertrophy and is required for myotube growth in vitro.

Resistance exercise training (RT) is the most effective method for increasing skeletal muscle mass in older adults; however, the amount of RT-induced muscle growth is highly variable between individuals. Recent evidence from our laboratory and others suggests ribosome biogenesis may be an important factor regulating RT-induced hypertrophy, and we hypothesized that the extent of hypertrophy is at least partly regulated by the amount of RT-induced ribosome biogenesis. To examine this, 42 older adults underwent 4 wk of RT aimed at inducing hypertrophy of the knee extensors (e.g., 2 sets of squat, leg press, and knee extension, 10-12 repetition maximums, 3 days/wk), and vastus lateralis muscle biopsies were performed pre- and post-RT. Post hoc K-means cluster analysis revealed distinct differences in type II myofiber hypertrophy among subjects. The percent change in type II myofiber size in nonresponders (Non; n = 17) was -7%, moderate responders (Mod; n = 19) +22%, and extreme responders (Xtr; n = 6) +83%. Total muscle RNA increased only in Mod (+9%, P < 0.08) and Xtr (+26%, P < 0.01), and only Xtr increased rRNA content (+40%, P < 0.05) and myonuclei/type II fiber (+32%, P < 0.01). Additionally, Mod and Xtr had a greater increase in c-Myc protein levels compared with Non (e.g., approximately +350 and +250% vs. +50%, respectively, P < 0.05). In vitro studies showed that growth factor-induced human myotube hypertrophy is abolished when rRNA synthesis is knocked down using the Pol I-specific inhibitor CX-5461. Overall, these data implicate ribosome biogenesis as a key process regulating the extent of RT-induced myofiber hypertrophy in older adults.

Histone Methylation Dynamics and Gene Regulation Occur through the Sensing of One-Carbon Metabolism.

S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) link one-carbon metabolism to methylation status. However, it is unknown whether regulation of SAM and SAH by nutrient availability can be directly sensed to alter the kinetics of key histone methylation marks. We provide evidence that the status of methionine metabolism is sufficient to determine levels of histone methylation by modulating SAM and SAH. This dynamic interaction led to rapid changes in H3K4me3, altered gene transcription, provided feedback regulation to one-carbon metabolism, and could be fully recovered upon restoration of methionine. Modulation of methionine in diet led to changes in metabolism and histone methylation in the liver. In humans, methionine variability in fasting serum was commensurate with concentrations needed for these dynamics and could be partly explained by diet. Together these findings demonstrate that flux through methionine metabolism and the sensing of methionine availability may allow direct communication to the chromatin state in cells.

Transforming Growth Factor Beta (TGF-ß) Is a Muscle Biomarker of Disease Progression in ALS and Correlates with Smad Expression.

We recently identified Smads1, 5 and 8 as muscle biomarkers in human ALS. In the ALS mouse, these markers are elevated and track disease progression. Smads are signal transducers and become activated upon receptor engagement of ligands from the TGF-ß superfamily. Here, we sought to characterize ligands linked to activation of Smads in ALS muscle and their role as biomarkers of disease progression. RNA sequencing data of ALS muscle samples were mined for TGF-ß superfamily ligands. Candidate targets were validated by qRT-PCR in a large cohort of human ALS muscle biopsy samples and in the G93A SOD1 mouse. Protein expression was evaluated by Western blot, ELISA and immunohistochemistry. C2C12 muscle cells were used to assess Smad activation and induction. TGF-ß1, 2 and 3 mRNAs were increased in ALS muscle samples compared to controls and correlated with muscle strength and Smads1, 2, 5 and 8. In the G93A SOD1 mouse, the temporal pattern of TGF-ß expression paralleled the Smads and increased with disease progression. TGF-ß1 immunoreactivity was detected in mononuclear cells surrounding muscle fibers in ALS samples. In muscle cells, TGF-ß ligands were capable of activating Smads. In conclusion, TGF-ß1, 2 and 3 are novel biomarkers of ALS in skeletal muscle. Their correlation with weakness in human ALS and their progressive increase with advancing disease in the ALS mouse suggest that they, as with the Smads, can track disease progression. These ligands are capable of upregulating and activating Smads and thus may contribute to the Smad signaling pathway in ALS muscle.

Muscle inflammation susceptibility: a prognostic index of recovery potential after hip arthroplasty?

While elective total hip arthroplasty (THA) for end-stage osteoarthritis (OA) improves pain, mobility function, and quality of life in most cases, a large proportion of patients suffer persistent muscle atrophy, pain, and mobility impairment. Extensive skeletal muscle damage is unavoidable in these surgical procedures, and it stands to reason that poor recovery and long-term mobility impairment among some individuals after THA is linked to failed muscle regeneration and regrowth following surgery and that local muscle inflammation susceptibility (MuIS) is a major contributing factor. Here we present results of two integrated studies. In study 1, we compared muscle inflammation and protein metabolism signaling in elective THA (n=15) vs. hip fracture/trauma (HFX; n=11) vs. nonsurgical controls (CON; n=19). In study 2, we compared two subgroups of THA patients dichotomized into MuIS⁺ (n=7) or MuIS⁻ (n=7) based on muscle expression of TNF-like weak inducer of apoptosis (TWEAK) receptor (Fn14). As expected, HFX demonstrated overt systemic and local muscle inflammation and hypermetabolism. By contrast, no systemic inflammation was detected in elective THA patients; however, local muscle inflammation in the perioperative limb was profound in MuIS⁺ and was accompanied by suppressed muscle protein synthesis compared with MuIS⁻. Muscle from the contralateral limb of MuIS⁺ was unaffected, providing evidence of a true inflammation susceptibility localized to the muscle surrounding the hip with end-stage OA. We suggest MuIS status assessed at the time of surgery may be a useful prognostic index for muscle recovery potential and could therefore provide the basis for a personalized approach to postsurgery rehabilitation.

Muscle fiber type, Achilles tendon length, potentiation, and running economy.

The purpose of this investigation was to develop a potential model for how muscle fiber type, Achilles tendon length, stretch-shortening cycle potentiation (SSCP), and leg strength interact with running economy. Twenty trained male distance runners 24-40 years of age served as subjects. Running economy (net oxygen uptake) was measured while running on a treadmill. Leg press SSCP(force) and SSCP(velocity) were determined by measuring the difference in velocity between a static leg press throw and a countermovement leg press throw. Vertical jump SSCP was determined by measuring the difference in jump height between a static jump and a drop jump from a 20.3-cm bench. Tendon length was measured by magnetic resonance imaging, and muscle fiber type was made from a vastus lateralis muscle biopsy. Type IIx muscle fiber percent (r = 0.70, p < 0.001) and leg strength (r = 0.95, p < 0.001) were positively and independently related to late eccentric force development. Achilles tendon length (r = 0.42, p ≤ 0.05) and late eccentric force during stretch-shortening cycle (r = 0.76, p < 0.001) were independently related to SSCP(force). SSCP(force) was related to SSCP(velocity), which in turn was related to running economy (r = 0.61, p < 0.01). These results suggest that longer Achilles tendon length, type II fiber, and muscular leg strength may enhance the potential for SSCP, running economy, and physiological effort while running.

Increased expression of atrogenes and TWEAK family members after severe burn injury in nonburned human skeletal muscle.

Severe burn induces rapid skeletal muscle proteolysis after the injury, which persists for up to 1 year and results in skeletal muscle atrophy despite dietary and rehabilitative interventions. The purpose of this research was to determine acute changes in gene expression of skeletal muscle mass regulators postburn injury. Specimens were obtained for biopsy from the vastus lateralis of a nonburned leg of eight burned subjects (6M, 2F: 34.8 ± 2.7 years: 29.9 ± 3.1% TBSA burn) at 5.1 ± 1.1 days postburn injury and from matched controls. mRNA expression of cytokines and receptors in the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) families, and the ubiquitin proteasome E3 ligases, atrogin-1 and MuRF-1, was determined. TNF receptor 1A was over 3.5-fold higher in burn. Expression of TNF-like weak inducer of apoptosis and its receptor were over 1.6 and 6.0-fold higher in burn. IL-6, IL-6 receptor, and glycoprotein 130 were elevated in burned subjects with IL-6 receptor over 13-fold higher. The level of suppressor of cytokine signaling-3 was also increased nearly 6-fold in burn. Atrogin-1 and MuRF-1 were more than 4- and 3-fold higher in burn. These results demonstrate for the first time that severe burn in humans has a remarkable impact on gene expression in skeletal muscle of a nonburned limb of genes that promote inflammation and proteolysis. Because these changes likely contribute to the acute skeletal muscle atrophy in areas not directly affected by the burn, in the future it will be important to determine the responsible systemic cues.

Skeletal muscle signaling associated with impaired glucose tolerance in spinal cord-injured men and the effects of contractile activity.

The mechanisms underlying poor glucose tolerance in persons with spinal cord injury (SCI), along with its improvement after several weeks of neuromuscular electrical stimulation-induced resistance exercise (NMES-RE) training, remain unclear, but presumably involve the affected skeletal musculature. We, therefore, investigated skeletal muscle signaling pathways associated with glucose transporter 4 (GLUT-4) translocation at rest and shortly after a single bout of NMES-RE in SCI (n = 12) vs. able-bodied (AB, n = 12) men. Subjects completed an oral glucose tolerance test during visit 1 and ≈90 NMES-RE isometric contractions of the quadriceps during visit 2. Muscle biopsies were collected before, and 10 and 60 min after, NMES-RE. We assessed transcript levels of GLUT-4 by quantitative PCR and protein levels of GLUT-4 and phosphorylated- and total AMP-activated protein kinase (AMPK)-α, CaMKII, Akt, and AS160 by immunoblotting. Impaired glucose tolerance in SCI was confirmed by higher (P < 0.05) plasma glucose concentrations than AB at all time points after glucose ingestion, despite equivalent insulin responses to the glucose load. GLUT-4 protein content was lower (P < 0.05) in SCI vs. AB at baseline. Main group effects revealed higher phosphorylation in SCI of AMPK-α, CaMKII, and Akt (P < 0.05), and Akt phosphorylation increased robustly (P < 0.05) following NMES-RE in SCI only. In SCI, low skeletal muscle GLUT-4 protein concentration may, in part, explain poor glucose tolerance, whereas heightened phosphorylation of relevant signaling proteins (AMPK-α, CaMKII) suggests a compensatory effort. Finally, it is encouraging to find (based on Akt) that SCI muscle remains both sensitive and responsive to mechanical loading (NMES-RE) even ≈22 yr after injury.