Dana M. Otzel

Long-term deficits in quadriceps strength and activation following anterior cruciate ligament reconstruction

OBJECTIVE Even some time after a ruptured ACL has been reconstructed thigh musculature atrophy, voluntary activation, and knee-extensor strength deficits may be encountered. The purpose of this study was to evaluate bilateral knee-extension strength, voluntary activation of the quadriceps, and thigh circumference in males and females with ACL reconstruction (ACLR). DESIGN AND PARTICIPANTS Within-subject and between-subject designs were used to evaluate 24 unilateral ACLR individuals and 23 controls. MAIN OUTCOME MEASURES Isokinetic knee-extension strength was assessed in ACLR participants while central activation ratio (CAR) and thigh circumference measures were obtained from both groups. RESULTS Knee-extensor strength deficits (p < .039) and lower CAR of the quadriceps were found in the ACLR limb compared to the uninvolved limb (p = .047). Extensor strength was greater in males (p < .001), however, CAR was not different between sexes (p = .086). No difference in voluntary activation was revealed among the ACLR limb, uninvolved limb, and control limb when compared as independent groups (p = .460). The strength deficits found in the ACLR limb are partly attributable to lower voluntary activation compared to the uninvolved leg, given that no difference was found in thigh circumference between legs. CONCLUSION Clinicians should consider the deficits in muscle function when returning patients to pre-injury activity levels.

Influence of Aromatase Inhibition on the Bone‐Protective Effects of Testosterone

The influence of the aromatase enzyme in androgen‐induced bone maintenance after skeletal maturity remains somewhat unclear. Our purpose was to determine whether aromatase activity is essential to androgen‐induced bone maintenance. Ten‐month‐old male Fisher 344 rats (n = 73) were randomly assigned to receive Sham surgery, orchiectomy (ORX), ORX + anastrozole (AN; aromatase inhibitor), ORX + testosterone‐enanthate (TE, 7.0 mg/wk), ORX + TE + AN, ORX + trenbolone‐enanthate (TREN; nonaromatizable, nonestrogenic testosterone analogue; 1.0 mg/wk), or ORX + TREN + AN. ORX animals exhibited histomorphometric indices of high‐turnover osteopenia and reduced cancellous bone volume compared with Shams. Both TE and TREN administration suppressed cancellous bone turnover similarly and fully prevented ORX‐induced cancellous bone loss. TE‐ and TREN‐treated animals also exhibited greater femoral neck shear strength than ORX animals. AN co‐administration slightly inhibited the suppression of bone resorption in TE‐treated animals but did not alter TE‐induced suppression of bone formation or the osteogenic effects of this androgen. In TREN‐treated animals, AN co‐administration produced no discernible effects on cancellous bone turnover or bone volume. ORX animals also exhibited reduced levator ani/bulbocavernosus (LABC) muscle mass and elevated visceral adiposity. In contrast, TE and TREN produced potent myotrophic effects in the LABC muscle and maintained fat mass at the level of Shams. AN co‐administration did not alter androgen‐induced effects on muscle or fat. In conclusion, androgens are able to induce direct effects on musculoskeletal and adipose tissue, independent of aromatase activity.

Testosterone inhibits expression of lipogenic genes in visceral fat by an estrogen-dependent mechanism

The influence of the aromatase enzyme on the chronic fat-sparing effects of testosterone requires further elucidation. Our purpose was to determine whether chronic anastrozole (AN, an aromatase inhibitor) treatment alters testosterone-mediated lipolytic/lipogenic gene expression in visceral fat. Ten-month-old Fischer 344 rats (n = 6/group) were subjected to sham surgery (SHAM), orchiectomy (ORX), ORX + treatment with testosterone enanthate (TEST, 7.0 mg/wk), or ORX + TEST + AN (0.5 mg/day), with drug treatment beginning 14 days postsurgery. At day 42, ORX animals exhibited nearly undetectable serum testosterone and 29% higher retroperitoneal fat mass than SHAM animals (P < 0.001). TEST produced a ∼380-415% higher serum testosterone than SHAM (P < 0.001) and completely prevented ORX-induced visceral fat gain (P < 0.001). Retroperitoneal fat was 21% and 16% lower in ORX + TEST than SHAM (P < 0.001) and ORX + TEST + AN (P = 0.007) animals, while serum estradiol (E2) was 62% (P = 0.024) and 87% (P = 0.010) higher, respectively. ORX stimulated lipogenic-related gene expression in visceral fat, demonstrated by ∼84-154% higher sterol regulatory element-binding protein-1 (SREBP-1, P = 0.023), fatty acid synthase (P = 0.01), and LPL (P < 0.001) mRNA than SHAM animals, effects that were completely prevented in ORX + TEST animals (P < 0.01 vs. ORX for all). Fatty acid synthase (P = 0.061, trend) and LPL (P = 0.043) mRNA levels were lower in ORX + TEST + AN than ORX animals and not different from SHAM animals but remained higher than in ORX + TEST animals (P < 0.05). In contrast, the ORX-induced elevation in SREBP-1 mRNA was not prevented by TEST + AN, with SREBP-1 expression remaining ∼117-171% higher than in SHAM and ORX + TEST animals (P < 0.01). Across groups, visceral fat mass and lipogenic-related gene expression were negatively associated with serum testosterone, but not E2 Aromatase inhibition constrains testosterone-induced visceral fat loss and the downregulation of key lipogenic genes at the mRNA level, indicating that E2 influences the visceral fat-sparing effects of testosterone.

Effects of pharmacologic sclerostin inhibition or testosterone administration on soleus muscle atrophy in rodents after spinal cord injury.

Sclerostin is a circulating osteocyte-derived glycoprotein that negatively regulates Wnt-signaling after binding the LRP5/LRP6 co-receptors. Pharmacologic sclerostin inhibition produces bone anabolic effects after spinal cord injury (SCI), however, the effects of sclerostin-antibody (Scl-Ab) on muscle morphology remain unknown. In comparison, androgen administration produces bone antiresorptive effects after SCI and some, but not all, studies have reported that testosterone treatment ameliorates skeletal muscle atrophy in this context. Our purposes were to determine whether Scl-Ab prevents hindlimb muscle loss after SCI and compare the effects of Scl-Ab to testosterone enanthate (TE), an agent with known myotrophic effects. Male Sprague-Dawley rats aged 5 months received: (A) SHAM surgery (T8 laminectomy), (B) moderate-severe contusion SCI, (C) SCI+TE (7.0 mg/wk, im), or (D) SCI+Scl-Ab (25 mg/kg, twice weekly, sc). Twenty-one days post-injury, SCI animals exhibited a 31% lower soleus mass in comparison to SHAM, accompanied by >50% lower soleus muscle fiber cross-sectional area (fCSA) (p<0.01 for all fiber types). Scl-Ab did not prevent soleus atrophy, consistent with the relatively low circulating sclerostin concentrations and with the 91–99% lower LRP5/LRP6 gene expressions in soleus versus tibia (p<0.001), a tissue with known anabolic responsiveness to Scl-Ab. In comparison, TE partially prevented soleus atrophy and increased levator ani/bulbocavernosus (LABC) mass by 30–40% (p<0.001 vs all groups). The differing myotrophic responsiveness coincided with a 3-fold higher androgen receptor gene expression in LABC versus soleus (p<0.01). This study provides the first direct evidence that Scl-Ab does not prevent soleus muscle atrophy in rodents after SCI and suggests that variable myotrophic responses in rodent muscles after androgen administration are influenced by androgen receptor expression.

Muscular responses to testosterone replacement vary by administration route: a systematic review and meta‐analysis

Inconsistent fat‐free mass (FFM) and muscle strength responses have been reported in randomized clinical trials (RCTs) administering testosterone replacement therapy (TRT) to middle‐aged and older men. Our objective was to conduct a meta‐analysis to determine whether TRT improves FFM and muscle strength in middle‐aged and older men and whether the muscular responses vary by TRT administration route.

Comparison of Metabolic Cost, Performance, and Efficiency of Propulsion Using an Ergonomic Hand Drive Mechanism and a Conventional Manual Wheelchair

OBJECTIVE To compare the metabolic cost (oxygen uptake per unit time [V˙o2 consumption], heart rate, and number of pushes), performance (velocity and distance traveled), and efficiency (oxygen uptake per distance traveled [Vo2 efficiency]) of propulsion using a novel ergonomic hand drive mechanism (EHDM) and a conventional manual wheelchair (CMW). DESIGN Repeated-measures crossover design. SETTING Semicircular track. PARTICIPANTS Adult full-time manual wheelchair users with spinal cord injuries (N=12; mean age ± SD, 38.8±12.4y; mean body mass ± SD, 73.7±13.3kg; mean height ± SD, 173.6±11.1cm) who were medically and functionally stable and at least 6 months postinjury. INTERVENTION Participants propelled themselves for 3.5 minutes at a self-selected pace in a CMW and in the same chair fitted with the EHDM. MAIN OUTCOME MEASURES Velocity, distance traveled, number of pushes, V˙o2 consumption, Vo2 efficiency, and heart rate were compared by wheelchair condition for the last 30 seconds of each trial using paired t tests (α=.01). RESULTS The CMW condition resulted in more distance traveled (33.6±10.8m vs 22.4±7.8m; P=.001), greater velocity (1.12±0.4m/s vs .75±.30m/s; P=.001), and better Vo2 efficiency (.10±.03mL·kg(-1)·m(-1) vs .15±.03mL·kg(-1)·m(-1); P<.001) than the EHDM condition, respectively. No significant differences were found between the 2 conditions for number of pushes (27.5±5.7 vs 25.7±5.4; P=.366), V˙o2 consumption (6.43±1.9mL·kg(-1)·min(-1) vs 6.19±1.7mL·kg(-1)·min(-1); P=.573), or heart rate (100.5±14.5 beats per minute vs 97.4±20.2 beats per minute; P=.42). CONCLUSIONS The results demonstrate that metabolic costs did not differ significantly; however, performance and efficiency were sacrificed with the EHDM. Modifications to the EHDM (eg, addition of gearing) could rectify the performance and efficiency decrements while maintaining similar metabolic costs. Although not an ideal technology, the EHDM can be considered as an alternative mode of mobility by wheelchair users and rehabilitation specialists.

Wheelchair ergonomic hand drive mechanism use improves wrist mechanics associated with carpal tunnel syndrome

Among conventional manual wheelchair (CMW) users, 49% to 63% experience carpal tunnel syndrome (CTS) that is likely induced by large forces transmitted through the wrist and extreme wrist orientations. The ergonomic hand drive mechanism (EHDM) tested in this study has been shown to utilize a more neutral wrist orientation. This study evaluates the use of an EHDM in terms of wrist orientations that may predispose individuals to CTS. Eleven adult full-time CMW users with spinal cord injury participated. Motion data were captured as participants propelled across a flat surface, completing five trials in a CMW and five trials in the same CMW fitted with the EHDM. Average angular wrist orientations were compared between the two propulsion styles. Use of the EHDM resulted in reduced wrist extension and ulnar deviation. The shift to more neutral wrist orientations observed with EHDM use may reduce median nerve compression.

Activity-Based Physical Rehabilitation with Adjuvant Testosterone to Promote Neuromuscular Recovery after Spinal Cord Injury

Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after SCI. However, ABT efficacy declines as SCI severity increases. Additionally, many men with SCI exhibit low testosterone, which may exacerbate neuromusculoskeletal impairment. Incorporating testosterone adjuvant to ABTs may improve musculoskeletal recovery and neuroplasticity because androgens attenuate muscle loss and the slow-to-fast muscle fiber-type transition after SCI, in a manner independent from mechanical strain, and promote motoneuron survival. These neuromusculoskeletal benefits are promising, although testosterone alone produces only limited functional improvement in rodent SCI models. In this review, we discuss the (1) molecular deficits underlying muscle loss after SCI; (2) independent influences of testosterone and locomotor training on neuromuscular function and musculoskeletal integrity post-SCI; (3) hormonal and molecular mechanisms underlying the therapeutic efficacy of these strategies; and (4) evidence supporting a multimodal strategy involving ABT with adjuvant testosterone, as a potential means to promote more comprehensive neuromusculoskeletal recovery than either strategy alone.

Motoneuron Function Does Not Change Following Whole-Body Vibration in Individuals With Chronic Ankle Instability

CONTEXT Following a lateral ankle sprain, ∼40% of individuals develop chronic ankle instability (CAI), characterized by recurrent injury and sensations of giving way. Deafferentation due to mechanoreceptor damage postinjury is suggested to contribute to arthrogenic muscle inhibition (AMI). Whole-body vibration (WBV) has the potential to address the neurophysiologic deficits accompanied by CAI and, therefore, possibly prevent reinjury. OBJECTIVE To determine if an acute bout of WBV can improve AMI and proprioception in individuals with CAI. DESIGN AND PARTICIPANTS The authors examined if an acute bout of WBV can improve AMI and proprioception in individuals with CAI with a repeated-measures design. A total of 10 young adults with CAI and 10 age-matched healthy controls underwent a control, sham, and WBV condition in randomized order. SETTING Biomechanics laboratory. INTERVENTION WBV. MAIN OUTCOME MEASURES Motoneuron pool recruitment was assessed via Hoffmann reflex (H-reflex) in the soleus. Proprioception was evaluated using ankle joint position sense at 15° and 20° of inversion. Both were assessed prior to, immediately following, and 30 minutes after the intervention (pretest, posttest, and 30mPost, respectively). RESULTS Soleus maximum H-reflex:M-response (H:M) ratios were 25% lower in the CAI group compared with the control group (P = .03). Joint position sense mean constant error did not differ between groups (P = .45). Error at 15° in the CAI (pretest 0.8 [1.6], posttest 2.0 [2.8], 30mPost 2.0 [1.9]) and control group (pretest 0.8 [2.0], posttest 0.6 [2.9], 30mPost 0.5 [2.1]) did not improve post-WBV. Error at 20° did not change post-WBV in the CAI (pretest 1.3 [1.7], posttest 1.0 [2.4], 30mPost 1.5 [2.2]) or control group (pretest -0.3 [3.0], posttest 0.8 [2.1], 30mPost 0.6 [1.8]). CONCLUSION AMI is present in the involved limb of individuals with CAI. The acute response following a single bout of WBV did not ameliorate the presence of AMI nor improve proprioception in those with CAI.

Longitudinal Examination of Bone Loss in Male Rats After Moderate–Severe Contusion Spinal Cord Injury

To elucidate mechanisms of bone loss after spinal cord injury (SCI), we evaluated the time-course of cancellous and cortical bone microarchitectural deterioration via microcomputed tomography, measured histomorphometric and circulating bone turnover indices, and characterized the development of whole bone mechanical deficits in a clinically relevant experimental SCI model. 16-weeks-old male Sprague–Dawley rats received T9 laminectomy (SHAM, n = 50) or moderate–severe contusion SCI (n = 52). Outcomes were assessed at 2-weeks, 1-month, 2-months, and 3-months post-surgery. SCI produced immediate sublesional paralysis and persistent hindlimb locomotor impairment. Higher circulating tartrate-resistant acid phosphatase 5b (bone resorption marker) and lower osteoblast bone surface and histomorphometric cancellous bone formation indices were present in SCI animals at 2-weeks post-surgery, suggesting uncoupled cancellous bone turnover. Distal femoral and proximal tibial cancellous bone volume, trabecular thickness, and trabecular number were markedly lower after SCI, with the residual cancellous network exhibiting less trabecular connectivity. Periosteal bone formation indices were lower at 2-weeks and 1-month post-SCI, preceding femoral cortical bone loss and the development of bone mechanical deficits at the distal femur and femoral diaphysis. SCI animals also exhibited lower serum testosterone than SHAM, until 2-months post-surgery, and lower serum leptin throughout. Our moderate–severe contusion SCI model displayed rapid cancellous bone deterioration and more gradual cortical bone loss and development of whole bone mechanical deficits, which likely resulted from a temporal uncoupling of bone turnover, similar to the sequalae observed in the motor-complete SCI population. Low testosterone and/or leptin may contribute to the molecular mechanisms underlying bone deterioration after SCI.