David W. Russ’s research while affiliated with University of South Florida and other places

Background: Following injury, older adults exhibit slow recovery of muscle function. Age-related impairment of sarcolemmal membrane repair may contribute to myocyte death, increasing the need for myogenesis and prolonging recovery. Dietary fish oil (FO) is a common nutritional supplement that may alter plasma membrane composition to enhance the response to membrane injury. Methods: We assessed effects of an 8-week dietary intervention on muscle contractile recovery in aged (22 mo.) rats on control (n = 5) or FO (control + 33 g/kg FO (45% eicosapentaenoic acid; 10% docosahexaenoic acid); n = 5) diets 1-week after contusion injury, as well as adult (8 mo., n = 8) rats on the control diet. Results: Recovery was reduced in aged rats on the control diet vs. adults (63 vs. 80%; p = 0.042), while those on the FO diet recovered similarly to (78%) adults. To directly assess sarcolemma injury, C2C12 cells were cultured in media with and without FO (1, 10, and 100 μg/mL; 24 or 48 h) and injured with an infrared laser in medium containing FM4-64 dye as a marker of sarcolemmal injury. FO reduced the area under the FM4-64 fluorescence-time curve at all concentrations after both 24 and 48 h supplementation. Conclusions: These preliminary data suggest FO might aid recovery of muscle function following injury in older adults by enhancing membrane resealing and repair.

Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility (i.e., weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is dual-energy x-ray absorptiometry (DXA), which quantifies areal bone mineral density (BMD), typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicates that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).

There is increasing appreciation of the role of rate of torque development (RTD) in physical function of older adults (OAs). This study compared various RTD strategies and electromyography (EMG) in the knee extensors and focused on discriminating groups with potential limitations in voluntary activation (VA) and associations of different RTD indices with functional tests that may be affected by VA in OAs. Neuromuscular function was assessed in 20 younger adults (YAs, 22.0 ± 1.7 years) and 50 OAs (74.4 ± 7.0 years). Isometric ballistic and peak torque during maximal voluntary contractions (pkTMVC), doublet stimulation and surface EMG were assessed and used to calculate VA during pkTMVC and RTD and rate of EMG rise during ballistic contractions. Select mobility tests (e.g., gait speed, 5× chair rise) were also assessed in the OAs. Voluntary RTD and RTD normalized to pkTMVC, doublet torque, and peak doublet RTD were compared. Rate of EMG rise and voluntary RTD normalized to pkTMVC did not differ between OAs and YAs, nor were they associated with functional test scores. Voluntary RTD indices normalized to stimulated torque parameters were significantly associated with VA (r = 0.319–0.459), and both indices were significantly lower in OAs vs YAs (all p < 0.020). These RTD indices showed significant association with the majority of mobility tests, but there was no clear advantage among them. Thus, voluntary RTD normalized to pkTMVC was ill-suited for use in OAs, while results suggests that voluntary RTD normalized to stimulated torque parameters may be useful for identifying central mechanisms of RTD impairment in OAs. Clinical trial registration number NCT02505529; date of registration 07/22/2015.

The voltage-gated potassium channels (Kv) are complex ion channels with distinct roles in neurotransmission, electrical conductivity of the heart, and smooth and striated muscle functions. Previously, we demonstrated that deletion of Kvβ2 in mice results in decreased Pax7 protein levels, hindlimb muscles and body weights, and fiber type switching. In the present study, we tested the hypothesis that Kvβ2 regulates skeletal muscle function in mice. The young and old Kvβ2 knockout (KO) and wildtype (WT) mice were utilized to test the aging phenotype and skeletal muscle function. Consistent with our previous finding, we found a significant reduction in hindlimb skeletal muscles mass and body weight in young Kvβ2 KO mice, which was also significantly reduced in old Kvβ2 KO mice compared with age-matched WT mice. Forelimb grip strength, and the hindleg extensor digitorum longus (EDL) muscles force-frequency relations were significantly decreased in young and old Kvβ2 KO mice compared to age-matched WT mice. Analysis of transmission electron microscopy images of EDL muscles in young mice revealed a significant reduction in the sarcomere length for Kvβ2 KO vs. WT. Hematoxylin and eosin-stained tibialis anterior muscles cryosections displayed a significant decrease in the number of medium (2,000–4,000 µm ² ) and largest (>4,000 µm ² ) myofibers area in young Kvβ2 KO vs. WT mice. We also found a significant increase in fibrotic tissue area in young Kvβ2 KO mice compared with age-matched WT mice. Analysis of RNA Seq data of the gastrocnemius muscles (GAS) identified significant increase in genes involved in skeletal muscle development, proliferation and cell fate determination, atrophy, energy metabolism, muscle plasticity, inflammation, and a decrease in circadian core clock genes in young Kvβ2 KO vs. WT mice. Several genes were significantly upregulated (384 genes) and downregulated (40 genes) in young Kvβ2 KO mice compared to age-matched WT mice. Further, RT-qPCR analysis of the GAS muscles displayed a significant increase in pro-inflammatory marker Il6 expression in young Kvβ2 KO mice compared to age-matched WT mice. Overall, the present study shows that deletion of Kvβ2 leads to decreased muscles strength and increased inflammation.

This study tests the effect of trimetazidine dihydrochloride (TMZ) on contractility in fast and slow skeletal muscles of adult (Ad, 6-8 mo.) and aged (Ag, 75% lifespan) male (M) and female (F) F344/BN rats. We hypothesized that TMZ would enhance contractility produced by indirect, but not direct, stimulation. Methods: Rats were injected with 3 mg/kg TMZ or vehicle 2x/d x 4 wk. Grip strength was assessed at the start and end of the protocol. Ex vivo force was tested at 4 wks in extensor digitorum longus (EDL) and soleus (SOL) at 3 frequencies (EDL: 1, 30, 120Hz; SOL: 1, 15, 60Hz) of direct/muscle and indirect/nerve stimulation. Fiber type was assessed via myosin heavy chain immunostaining. Results: Indirect vs. Direct Stimulation : Higher forces were seen with direct vs. indirect stimulation (P ≤ 0.002). Only tetanic stimulation (120 & 60 Hz, EDL & SOL, respectively) showed effects of age, sex or TMZ on the ratio of indirect/direct stimulation force, which was reduced with age (SOL: 4.9%, P = 0.038; EDL: 5.1%, P = 0.052). EDL Force : Force, but not muscle quality (force/cross-sectional area), was lower in F at all frequencies. No effects of age or TMZ were present for either force or muscle quality. Force at 1 and 120Hz exhibited significant Age X Sex interactions (P = 0.029 & 0.013). Age X Sex X TMZ interaction was significant at 30 and 120Hz (P = 0.028 & 0.046). In contrast, only muscle quality at 120-Hz exhibited any effects (P = 0.024; Age x Sex), There was also a trend (P = 0.067) for TMZ to reduce muscle quality at 120-Hz stimulation. The general trend was for Ag M to exhibit reduced force and muscle quality vs. Ad M, with increases in Ag vs. Ad F. SOL Force : A significant effect of sex on peak force was present at all frequencies tested. An effect for TMZ was present at 60-Hz (P = 0.024), largely due to lower force in TMZ-treated F. Muscle quality showed a main effect of TMZ and the Sex X TMZ interaction (P = 0.007 & 0.048,), due reductions in TMZ-treated F. Grip Strength : An age X sex interaction was found (P = 0.012), but TMZ exhibited only trends for interaction effects (Age x TMZ, P = 0.084; Time x Age x Sex x TMZ, P = 0.062). Grip strength normalized to body mass, showed a similar Time x Age x Sex x TMZ interaction (P = 0.062). Fiber Type : Effect of Sex and a Sex X TMZ interaction were observed for percent Type IIa and Type IIb fibers in the EDL. TMZ tended to increase % IIa fibers in M, while decreasing it in F, with the reverse seen for % Type IIb fibers. Conclusions: Indirect/direct stimulation data suggest age-related impairment in peripheral neural activation that is not affected by TMZ. TMZ improved grip less than in previous studies and produced smaller effects on contractility than sex or age. In fact, TMZ tended to reduce contractility, particularly in the SOL. However, TMZ did influence EDL fiber type in a sex-dependent manner which may influence differences in contractility. NIH/NIA R03 AG060143-01A1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

There is increasing interest in using motor function tests to identify risk of cognitive impairment in older adults (OA). This study examined associations among grip strength, with and without adjustment for muscle mass, manual dexterity and Trail Making Test (TMT) A and B in 77 OA (73.4 ± 5.2 years) with globally intact cognition. A subset of OA who exhibited mismatched motor function (e.g., in the highest strength and lowest dexterity tertiles, or vice versa) was identified and analyzed. Dexterity showed stronger associations with TMT-A and -B than grip strength (absolute or adjusted). OA with mismatched motor function scored worse on tests of TMT-B, but not -A than those with matched motor function. Dexterity may have more promise than grip strength for identifying increased risk of cognitive impairment. Intriguing, though limited, data suggest that mismatched motor function (strength vs. dexterity) in OAs might be an even more robust marker of such risk.

This study aimed to describe changes in forelimb grip strength and ex vivo muscle force production in adult (Ad) and aged (Ag, 75% lifespan) male (M) and female (F) F344/BN hybrid rats. We hypothesized that differences in M vs. F would be explained by muscle mass, but that age differences would persist after normalizing to mass in fast, but not slow muscles. Forelimb grip was expressed in absolute terms (Grip) and relative to body mass (NGrip). Ex vivo forces of the extensor digitorum longus (EDL) and Soleus (Sol) were assessed at 3 stimulation frequencies and 2 pulse durations, and expressed as absolute muscle force (AMF) and muscle quality (MQ; force/anatomical cross-sectional area). We also assessed sarcoplasmic reticulum (SR) Ca2+ release and reuptake from homogenates of both muscles. Body mass was higher in Ag vs. Ad and M vs. F (both p < 0.001), while EDL and Sol mass were smaller in F vs. M (p < 0.001), with no effect of age. Grip showed no effect of age, but was significantly (p < 0.001) lower in F while NGrip was higher in Ad vs. Ag (p < 0.001) and F vs. M (p < 0.001). EDL AMF exhibited a significant age X sex interaction (p = 0.006) across frequencies, as AMF declined with age in M, but increased in F. EDL MQ showed a similar pattern (p = 0.039), but only at the highest frequency (120Hz). In Sol, M showed a trend (p = 0.078) for higher AMF relative to F. In contrast, MQ was significantly higher in F vs. M (p = 0.025). Differences in SR function did not appear to contribute to these differences as the only significant effect observed was for SR Ca2+ uptake to be reduced in F vs. M in both EDL and Sol (p = 0.046 & 0.050, respectively). These findings indicate that grip and isolated muscle contractility are generally higher in M vs. F when expressed in absolute terms, but lower in M vs. F when expressed as relative measures (normalized to body mass or muscle size). Minimal declines in muscle contractility occurred with age in either muscle tested, consistent with what we have observed previously with in situ testing of the Sol, but other aged fast muscles.

Background: Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6-dibromo-α-[(phenylamino)methyl]-9H-carbazol-9-ethanol) ameliorates diabetes and muscle function. Methods: We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice. Nampt+/- mice were utilized to test the specificity of P7C3. Results: Insulin resistance increased 1.6-fold in diabetic mice compared with wild-type mice and after 4 weeks treatment with P7C3 rescued diabetes (P < 0.05). In the db-P7C3 mice fasting blood glucose levels decreased to 0.96-fold compared with C57Bl/6J wild-type naïve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6-fold and 0.54-folds, respectively, at 120 min along with an increase in insulin secretion (1.76-fold) and pancreatic β-cells (3.92-fold) in db-P7C3 mice. The fore-limb and hind-limb grip strengths were increased to 1.13-fold and 1.17-fold, respectively, together with a 14.2-fold increase in voluntary running wheel distance in db-P7C3 mice. P7C3 treatment resulted in a 1.4-fold and 7.1-fold increase in medium-sized and larger-sized myofibres cross-sectional area, with a concomitant 0.5-fold decrease in smaller-sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67-fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9-fold decrease in mitochondrial area in db-P7C3 mice compared with db-Veh mice. The number of SDH positive myofibres were increased to 1.74-fold in db-P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46-fold) and immunostaining (6.4-fold), respectively. qPCR analysis displayed a 2.9-fold and 1.3-fold increase in Pdk4 and Cpt1, and 0.55-fold and 0.59-fold decrease in Fgf21 and 16S in db-P7C3 mice. There was also a 3.3-fold and 1.9-fold increase in Fabp1 and CD36 in db-Veh mice. RNA-seq differential gene expression volcano plot displayed 1415 genes to be up-regulated and 1726 genes down-regulated (P < 0.05) in db-P7C3 mice. There was 1.02-fold increase in serum HDL, and 0.9-fold decrease in low-density lipoprotein/very low-density lipoprotein ratio in db-P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n-6; AA (0.83-fold), and n-3; DHA (0.69-fold) and EPA (0.81-fold), and a 0.66-fold decrease in endocannabinoid 2-AG and 2.0-fold increase in AEA in db-P7C3 mice. Conclusions: Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db/db mice.