Low‐intensity running exercise enhances the capillary volume and pro‐angiogenic factors in the soleus muscle of type 2 diabetic rats

Introduction: We determined the effects of low‐intensity exercise on the three‐dimensional capillary structure and associated angiogenic factors in the soleus muscle of Goto‐Kakizaki (GK) diabetic rats. Methods: Four groups of male rats were studied: sedentary nondiabetic (Con), exercised nondiabetic control (Ex), sedentary GK, and exercised GK (GK+Ex). Rats in the Ex and GK+Ex groups were subjected to chronic low‐intensity running on a treadmill (15 m/min, 60 min/session, 5 sessions/week for 3 weeks). Results: Although mean capillary volume and diameter were lower in the GK compared with all other groups, low‐intensity exercise increased both of these measures in GK rats. Mitochondrial markers, i.e., SDH activity and PGC‐1α expression, and the levels of angiogenic factors were higher in the GK+Ex than all other groups. Exercise increased vascular endothelial growth factor (VEGF) protein levels and the VEGF‐to‐TSP‐1 ratio, an indicator of angiogenesis, in GK rats. Conclusions: Combined, the results indicate that low‐intensity exercise reduces some of the microcirculatory complications in type 2 diabetic muscles. Muscle Nerve 51: 391–399, 2015     

Effect of resistance training on neuromuscular junctions of young and aged muscles featuring different recruitment patterns

To examine the effects of aging on neuromuscular adaptations to resistance training (i.e., weight lifting), young (9 months of age) and aged (20 months of age) male rats either participated in a 7‐week ladder climbing protocol with additional weight attached to their tails or served as controls (n = 10/group). At the conclusion, rats were euthanized and hindlimb muscles were quickly removed and frozen for later analysis. Longitudinal sections of the soleus and plantaris muscles were collected, and pre‐ and postsynaptic features of neuromuscular junctions (NMJs) were visualized with immunofluorescence staining procedures. Cross‐sections of the same muscles were histochemically stained to determine myofiber profiles (fiber type and size). Statistical analysis was by two‐way ANOVA (main effects of age and treatment) with significance set at P ≤ 0.05. Results revealed that training‐induced remodeling of NMJs was evident only at the postsynaptic endplate region of soleus fast‐twitch myofibers. In contrast, aging was associated with pre‐ and postsynaptic remodeling in fast‐ and slow‐twitch myofibers of the plantaris. Although both the soleus and the plantaris muscles failed to display either training or aging‐related alterations in myofiber size, aged plantaris muscles exhibited an increased expression of type I (slow‐twitch) myofibers in conjunction with a reduced percentage of type II (fast‐twitch) myofibers, suggesting early stages of sarcopenia. These data demonstrate the high degree of specificity of synaptic modifications made in response to exercise and aging and that the sparsely recruited plantaris is more vulnerable to the effects of aging than the more frequently recruited soleus muscle. © 2014 Wiley Periodicals, Inc.     

Effects of exercise and muscle type on BDNF,NT‐4/5, and TrKB expression in skeletal muscle

Muscle‐derived neurotrophins are thought to contribute to the adaptation of skeletal muscle to exercise, but the effects of brief exercise interventions on BDNF, NT‐4/5, and trkB are not understood. RNA was extracted for RT‐PCR from soleus and medial gastrocnemius of Sprague‐Dawley rats exercised on a treadmill at speeds up to 20 m/min at 5% incline for 5 or 10 days. BDNF expression was elevated in soleus following 5 days (184%, P < 0.001) but not 10 days of exercise. NT‐4/5 and trkB were not affected at either time‐point. BDNF mRNA was significantly higher in soleus at rest when compared with medial gastrocnemius (193%, P < 0.05). No significant effects of muscle type were detected for NT‐4/5 and trkB. Our results indicate differential control of BDNF expression between soleus and medial gastrocnemius following 5 days of exercise. BDNF may be a protein with an uncharacterized contribution to the acute adaptation of skeletal muscle to exercise, whereas NT‐4/5 shows no response. Muscle Nerve, 2009     

Inflammatory response during slow‐ and fast‐twitch muscle regeneration

Introduction: Skeletal muscles are characterized by their unique ability to regenerate. Injury of a so‐called fast‐twitch muscle, extensor digitorum longus (EDL), results in efficient regeneration and reconstruction of the functional tissue. In contrast, slow‐twitch muscle (soleus) fails to properly reconstruct and develops fibrosis. This study focuses on soleus and EDL muscle regeneration and associated inflammation. Methods: We determined differences in the activity of neutrophils and M1 and M2 macrophages using flow cytometry and differences in the levels of proinflammatory cytokines using Western blotting and immunolocalization at different times after muscle injury. Results: Soleus muscle repair is accompanied by increased and prolonged inflammation, as compared to EDL. The proinflammatory cytokine profile is different in the soleus and ED muscles. Conclusions: Muscle repair efficiency differs by muscle fiber type. The inflammatory response affects the repair efficiency of slow‐ and fast‐twitch muscles. Muscle Nerve 55 : 400–409, 2017     

Memory and brain-derived neurotrophic factor after subchronic or chronic amphetamine treatment in an animal model of mania

Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala.     

Lingual and palatal gustatory afferents each depend on both BDNF and NT‐4, but the dependence is greater for lingual than palatal afferents

Neurons of the geniculate ganglion innervate taste buds located in two spatially distinct targets, the tongue and palate. About 50% of these neurons die in Bdnf^−/− mice and Ntf4/5^−/− mice. Bdnf^−/−/Ntf4/5^−/− double mutants lose 90–95% of geniculate ganglion neurons. To determine whether different subpopulations are differentially influenced by neurotrophins, we quantified neurons from two ganglion subpopulations separately and remaining taste buds at birth within each target field in wild‐type, Bdnf^−/−, Ntf4/5^−/−, and Bdnf^−/−/Ntf4/5^−/− mice. In wild‐type mice the same number of neurons innervated the anterior tongue and soft palate and each target contained the same number of taste buds. Compared to wild‐type mice, Bdnf^−/− mice showed a 50% reduction in geniculate neurons innervating the tongue and a 28% loss in neurons innervating the soft palate. Ntf4/5^−/− mice lost 58% of the neurons innervating the tongue and 41% of the neurons innervating the soft palate. Taste bud loss was not as profound in the NT‐4 null mice compared to BDNF‐null mice. Tongues of Bdnf^−/−/Ntf4/5^−/− mice were innervated by 0 to 4 gustatory neurons and contained 3 to 16 taste buds at birth, indicating that some taste buds remain even when all innervation is lost. Thus, gustatory neurons are equally dependent on BDNF and NT‐4 expression for survival, regardless of what peripheral target they innervate. However, taste buds are more sensitive to BDNF than NT‐4 removal. J. Comp. Neurol. 518:3290–3301, 2010. © 2010 Wiley‐Liss, Inc.     

Reduced brain‐derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF‐immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum

Spinocerebellar ataxia type 6 (SCA6) is an autosomal‐dominant neurodegenerative disorder caused by a small expansion of tri‐nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α_1A voltage‐dependent calcium channel (Ca_v2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75‐kDa carboxy‐terminal fragment (CTF) of Ca_v2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain‐derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT‐PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum (n = 3) compared to controls (n = 6) (Mann–Whitney U‐test, P = 0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF‐immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF‐immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2‐positive Ca_v2.1 aggregates existed more proximally than the BDNF‐positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Ca_v2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.     

Brain‐derived neurotrophic factor is upregulated in the cervical dorsal root ganglia and spinal cord and contributes to the maintenance of pain from facet joint injury in the rat

The facet joint is commonly associated with neck and low back pain and is susceptible to loading‐induced injury. Although tensile loading of the cervical facet joint has been associated with inflammation and neuronal hyperexcitability, the mechanisms of joint loading‐induced pain remain unknown. Altered brain‐derived neurotrophic factor (BDNF) levels are associated with a host of painful conditions, but the role of BDNF in loading‐induced joint pain remains undefined. Separate groups of rats underwent a painful cervical facet joint distraction or a sham procedure. Bilateral forepaw mechanical hypersensitivity was assessed and BDNF mRNA and protein levels were quantified in the dorsal root ganglion (DRG) and spinal cord at days 1 and 7. Facet joint distraction induced significant (P < 0.001) mechanical hypersensitivity at both time points. Painful joint distraction did not alter BDNF mRNA in the DRG compared with sham levels but did significantly increase (P < 0.016) BDNF protein expression over sham in the DRG at day 7. Painful distraction also significantly increased BDNF mRNA (P = 0.031) and protein expression (P = 0.047) over sham responses in the spinal cord at day 7. In a separate study, intrathecal administration of the BDNF‐sequestering molecule trkB‐Fc on day 5 after injury partially attenuated behavioral sensitivity after joint distraction and reduced pERK in the spinal cord at day 7 (P < 0.045). Changes in BDNF after painful facet joint injury and the effect of spinal BDNF sequestration in partially reducing pain suggest that BDNF signaling contributes to the maintenance of loading‐induced facet pain but that additional cellular responses are also likely involved. © 2013 Wiley Periodicals, Inc.     

Social defeat stress induces hyperalgesia and increases truncated BDNF isoforms in the nucleus accumbens regardless of the depressive‐like behavior induction in mice

Epidemiological studies have shown a close association between pain and depression. There is evidence showing this association as patients with depression show a high chronic pain prevalence and vice versa. Considering that social stress is critical for the development of depression in humans, we used a social defeat stress (SDS) model which induces depressive‐like behavior in mice. In this model, mice are exposed to an aggressor mouse for ten days, suffering brief periods of agonistic contact and long periods of sensory contact. Some mice display social avoidance, a depressive‐like behavior, and are considered susceptible, while some mice do not, and are considered resilient. Thus, we investigated the nociceptive behavior of mice submitted to SDS and the neuroplastic changes in dopaminergic mesolimbic system. Our results showed that the stressed mice (resilient and susceptible) presented a higher sensitivity to pain than the control mice in chemical and mechanical tests. We also verified that susceptible mice have higher Bdnf mRNA in the VTA compared to the resilient and control mice. The stressed mice had less mature BDNF and more truncated BDNF protein in the NAc compared with control mice. Although social stress may trigger the development of depression and hyperalgesia, these two conditions may manifest independently as social stress induced hyperalgesia even in mice that did not display depressive‐like behavior. Also, increased Bdnf in the VTA seems to be associated with depressive‐like behavior, whereas high levels of truncated BDNF and low mature BDNF appear to be associated with hyperalgesia induced by social defeat stress.     

The orbitofrontal cortex regulates outcome‐based decision‐making via the lateral striatum

The orbitofrontal cortex (oPFC) sends substantial projections to the ventrolateral striatum and aspects of the nucleus accumbens that are, functionally, poorly understood. This is despite probable cortico‐striatal involvement in multiple diseases such as addiction and obsessive‐compulsive disorder. Here we surgically disconnected the oPFC from the ventrolateral striatum using unilateral asymmetric lesions in mice and classified instrumental decision‐making strategies. Mice with symmetric lesions that spared one oPFC–striatal network served as controls. As a complementary approach, we selectively knocked down Brain‐derived neurotrophic factor (Bdnf) bilaterally in the oPFC and ascertained behavioral and neurobiological consequences within the downstream striatum. oPFC–striatal disconnection and oPFC Bdnf knockdown blocked sensitivity to outcome‐predictive relationships in both food‐reinforced and cocaine‐associated settings. Bdnf knockdown simultaneously regulated striatal BDNF expression, and striatal c‐Fos predicted sensitivity to action–outcome associative contingencies. Previous evidence strongly implicates the dorsolateral striatum in stimulus–response habit formation. Our findings thus provide novel evidence for functional compartmentalisation within the lateral striatum, with the dorsal compartment subserving classical stimulus–response habit systems and a ventral compartment coordinating outcome‐based decision‐making via oPFC interactions. This compartmentalisation may apply to both ‘natural’, as in the case of food‐reinforced behavior, and ‘pathological’, as in the case of cocaine‐seeking, contexts.     

Soleus and lateral gastrocnemius H‐reflexes during standing with unstable footwear

Introduction: Unstable footwear has been shown to increase lower extremity muscle activity, but the reflex response to perturbations induced by this intervention is unknown. Methods: Twenty healthy subjects stood in stable and unstable footwear conditions (presented randomly) while H‐reflex amplitude and background muscle activity were measured in the soleus and lateral gastrocnemius (LG) muscles. Results: Wearing unstable footwear resulted in larger H‐reflexes (normalized to the maximal M‐wave) for the LG (+12%; P = 0.025), but not for the soleus (+4%; P > 0.05). Background activity of both muscles was significantly higher in the unstable condition. Conclusions: The H‐reflex facilitation observed with unstable footwear was unexpected, as challenging postural conditions usually result in reflex depression. Increased muscle activity, decreased presynaptic inhibition, and/or more forward postural position may have (over‐)compensated the expected reflex depression. Differences between LG and soleus H‐reflex modulation may be due to diverging motor unit recruitment thresholds. Muscle Nerve 51 :764–766, 2015     

Serum brain‐derived neurotrophic factor and interleukin‐6 response to high‐volume mechanically demanding exercise

Introduction: The aim of this study was to follow circulating brain‐derived neurotrophic factor (BDNF) and interleukin‐6 (IL‐6) levels in response to severe muscle‐damaging exercise. Methods: Young healthy men (N = 10) performed a bout of mechanically demanding stretch–shortening cycle exercise consisting of 200 drop jumps. Voluntary and electrically induced knee extension torque, serum BDNF levels, and IL‐6 levels were measured before and for up to 7 days after exercise. Results: Muscle force decreased by up to 40% and did not recover by 24 hours after exercise. Serum BDNF was decreased 1 hour and 24 hours after exercise, whereas IL‐6 increased immediately and 1 hour after but recovered to baseline by 24 hours after exercise. IL‐6 and 100‐Hz stimulation torque were correlated (r = ?0.64, P < 0.05) 24 hours after exercise. Discussion: In response to acute, severe muscle‐damaging exercise, serum BDNF levels decrease, whereas IL‐6 levels increase and are associated with peripheral fatigue. Muscle Nerve 57 : E46–E51, 2018     

Physical exercise during muscle regeneration improves recovery of the slow/oxidative phenotype

Introduction: As skeletal muscle mass recovery after extensive injury is improved by contractile activity, we explored whether concomitant exercise accelerates recovery of the contractile and metabolic phenotypes after muscle injury. Methods: After notexin‐induced degeneration of a soleus muscle, Wistar rats were assigned to active (running exercise) or sedentary groups. Myosin heavy chains (MHC), metabolic enzymes, and calcineurin were studied during muscle regeneration at different time points. Results: The mature MHC profile recovered earlier in active rats (21 days after injury) than in sedentary rats (42 days). Calcineurin was higher in the active degenerated than in the sedentary degenerated muscles at day 14. Citrate synthase and total lactate dehydrogenase (LDH) activity decreased after injury and were similarly recovered in both active and sedentary groups at 14 or 42 days, respectively. H‐LDH isozyme activity recovered earlier in the active rats. Conclusions: Exercise improved recovery of the slow/oxidative phenotype after soleus muscle injury. Muscle Nerve 55 : 91–100, 2017     

Effects of exercise in a relapsing‐remitting model of experimental autoimmune encephalomyelitis

Previous research has examined the effects of exercise in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. However, all previous studies have utilized a chronic model of EAE, with exercise delivered prior to or immediately after induction of EAE. To our knowledge, no study has examined the effects of exercise delivered during a remission period after initial disease onset in a relapsing‐remitting model of EAE (RR‐EAE). The current study examines the effects of both voluntary wheel running and forced treadmill exercise on clinical disability and hippocampal brain‐derived neurotrophic factor (BDNF) in SJL mice with RR‐EAE. The results demonstrate no significant effects of exercise delivered during remission after initial disease onset on clinical disability scores or levels of hippocampal BDNF in mice with RR‐EAE. Furthermore, our results demonstrate no significant increase in citrate synthase activity in the gastrocnemius and soleus muscles of mice in the running wheel or treadmill conditions compared with the sedentary condition. These results suggest that the exercise stimuli might have been insufficient to elicit differences in clinical disability or hippocampal BDNF among treatment conditions. © 2016 Wiley Periodicals, Inc.     

Plasma BDNF and tPA are associated with late‐onset geriatric depression

Aims: Studies in the recent decade have shown that brain‐derived neurotrophic factor (BDNF) may play an important role in the pathogenesis of major depressive disorder (MDD). Tissue‐type plasminogen activator (tPA) has been implicated in the control of the direction of BDNF action. The aim of the study was therefore to investigate the changes of BDNF/tPA levels and their clinical meanings in geriatric depression. Methods: Plasma BDNF and tPA levels were measured in late‐onset geriatric depression (LGD) before treatment (n = 24) and after 6 weeks of antidepressant treatment (n = 24) compared with control subjects (n = 30) using enzyme‐linked immunosorbent assay. The severity of depression was assessed with the Hamilton Depression Rating Scale. Results: Baseline plasma BDNF and tPA levels were significantly lower in LGD patients compared to controls (P = 0.037 and P = 0.000, respectively). There was a heightening tendency of plasma BDNF level after treatment. Conclusions: Plasma BDNF and tPA levels are associated with LGD. The complex mechanism of BDNF and tPA in LGD should be further explored in future studies.     

Muscle proteins during 60‐day bedrest in women: Impact of exercise or nutrition

Almost no data exist regarding skeletal muscle responses to real or simulated spaceflight in women. We determined the impact of 60‐day bedrest (BR, n = 8), 60‐day bedrest with exercise‐training (BRE, n = 8), and 60‐day bedrest with a leucine‐enriched, high‐protein diet (BRN, n = 8) on muscle protein composition. Vastus lateralis and soleus muscle biopsies were analyzed for global protein fractions (mixed, sarcoplasmic, myofibrillar) and force‐specific proteins (myosin, actin, collagen). Concentrations (micrograms per milligram muscle wet weight) of these proteins were maintained (P > 0.05) in BR, despite large changes in quadriceps (?21%) and triceps surae (?29%) volume. Neither countermeasure influenced muscle protein content in either muscle (P > 0.05), despite exacerbation (BRN) or prevention (BRE) of atrophy. Pre‐bedrest comparisons showed less myofibrillar protein in the soleus (?16%, P < 0.05), primarily due to less myosin (?12%, P < 0.05) and more collagen (234%, P < 0.05) than the vastus lateralis. Muscle protein composition is tightly regulated in lower limb muscles of women, despite the most extreme weightlessness‐induced atrophy reported in humans. In contrast, men who underwent prolonged unloading were unable to proportionally regulate atrophy of the soleus. These findings have implications for astronauts and clinical conditions of sarcopenia regarding the maintenance of muscle function and prevention of frailty. Muscle Nerve, 2008     

Brain‐derived neurotrophic factor expression is increased in the hippocampus of 5‐HT2C receptor knockout mice

Several studies have suggested a close interaction between serotonin (5‐HT) and BDNF; however, little is known of the specific relationship between BDNF and the 5‐HT_2C receptor. Therefore, in this study we investigated BDNF expression in 5‐HT_2C receptor knockout mice (5‐HT_2CKO). We also assessed functional consequences of any changes in BDNF using a behavioral test battery. Western blot analysis demonstrated a significant 2.2‐fold increase in the expression of the mature form of BDNF in 5‐HT_2CKO mice when compared with wild‐type controls (WT) in the hippocampus (P = 0.008), but not frontal cortex or striatum. No differences in the expression of the pro‐BDNF isoform were found, and the ratio of mature/pro BDNF was significantly increased in 5‐HT_2CKO (P = 0.003). BDNF mRNA expression in the hippocampus was not different between the genotypes. Hence, increased mature BDNF levels in 5‐HT_2CKO hippocampus are most likely due to increased extracellular cleavage rates of pro‐BDNF to its mature form. Protein expression of the BDNF receptor, tropomycin‐related receptor B (TrkB), was also unchanged in the hippocampus, frontal cortex and striatum. With repeated training in a 10‐day win‐shift radial arm maze task, 5‐HT_2CKO and WT showed similar decreases of the number of working memory and reference memory errors. In addition, no genotype specific differences were observed for passive or active avoidance learning. 5‐HT_2CKO showed modest locomotor hyperactivity but no differences in tests for anxiety, sensorimotor gating, or depressive‐like behaviors; however, in the tail suspension test 5‐HT_2CKO showed significantly reduced climbing (P < 0.05). In conclusion, loss of 5‐HT_2C receptor expression leads to a marked and selective increase in levels of the mature form of BDNF in the hippocampus. Despite this marked increase, 5‐HT_2CKO show only subtle behavioral changes. © 2010 Wiley‐Liss, Inc.     

Selectively reshaping a muscle phenotype: functional overload of cat plantaris

Introduction: Functional overload (FO) of the fast plantaris muscle was studied in treadmill‐exercised (FO‐Ex) or sedentary (FO‐Sed) adult cats. Methods: Mechanical, phenotype, and kinematics analyses were performed. Results: Plantigrade vs. normal digitigrade posture was observed early post‐FO. Relative plantaris mass was greater in FO‐Sed (10%) and FO‐Ex (60%) cats than in controls 12 weeks post‐FO. Specific tension was similar across groups, indicating functional hypertrophy. Fiber size was greater, percent slow fibers higher, percent IIa myosin heavy chain (MHC) higher, and IIx MHC lower in FO‐Ex than controls. Twitch and half‐relaxation times were longer, and the frequency–tension curve shifted toward that observed in slow muscles. Electromyography (EMG) and tendon force amplitudes during stepping were larger, and the yield (lengthening) phase occurred at a longer muscle length before compared with after FO. Discussion: Reshaping the plantaris phenotype was highly dependent on the overload stimulus, indicating that electrical stimulation paradigms used during rehabilitation should be performed with the muscles under “loaded” conditions. Muscle Nerve, 2011     

Contractile properties of slow and fast skeletal muscles from protease activated receptor‐1 null mice

Introduction: Protease‐activated receptors (PARs) may play a role in skeletal muscle development. We compared the contractile properties of slow‐twitch soleus muscles and fast‐twitch extensor digitorum longus (EDL) muscles from PAR‐1 null and littermate control mice. Methods: Contractile function was measured using a force transducer system. Fiber type proportions were determined using immunohistochemistry. Results: Soleus muscles from PAR‐1 null mice exhibited longer contraction times, a leftward shift in the force–stimulation frequency relationship, and decreased fatiguability compared with controls. PAR‐1 null soleus muscles also had increased type 1 and decreased type IIb/x fiber numbers compared with controls. In PAR‐1 null EDL muscles, no differences were found, except for a slower rate of fatigue compared with controls. Conclusions: The absence of PAR‐1 results in a slower skeletal muscle contractile phenotype, likely due to an increase in type I and a decrease in type IIb/x fiber numbers. Muscle Nerve 50: 991–998, 2014