Mechanical and strain behaviour of human Achilles tendon during in vitro testing to failure.

The Achilles tendon is the strongest tendon in the human body but its mechanical behaviour during failure has been little studied and the basis of its high tensile strength has not been elucidated in detail. In the present study, healthy, human, Achilles tendons were loaded to failure in an anatomically authentic fashion while the local deformation and strains were studied in real time, with very high precision, using digital image correlation (DIC). The values determined for the strength of the Achilles tendon were at the high end of those reported in the literature, consistent with the absence of a pre-existing tendinopathy in the samples, as determined by careful gross inspection and histology. Early in the loading cycle, the proximal region of the tendon accumulated high lateral strains while longitudinal strains remained low. However, immediately before rupture, the mid-substance of the Achilles tendon, its weakest part, started to show high longitudinal strains. These new insights advance the understanding of the mechanical behaviour of tendons as they are stretched to failure.

Exercise-driven metabolic pathways in healthy cartilage.

OBJECTIVE: Exercise is vital for maintaining cartilage integrity in healthy joints. Here we examined the exercise-driven transcriptional regulation of genes in healthy rat articular cartilage to dissect the metabolic pathways responsible for the potential benefits of exercise. METHODS: Transcriptome-wide gene expression in the articular cartilage of healthy Sprague-Dawley female rats exercised daily (low intensity treadmill walking) for 2, 5, or 15 days was compared to that of non-exercised rats, using Affymetrix GeneChip arrays. Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO)-term enrichment and Functional Annotation analysis of differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genome (KEGG) pathway mapper was used to identify the metabolic pathways regulated by exercise. RESULTS: Microarray analysis revealed that exercise-induced 644 DEGs in healthy articular cartilage. The DAVID bioinformatics tool demonstrated high prevalence of functional annotation clusters with greater enrichment scores and GO-terms associated with extracellular matrix (ECM) biosynthesis/remodeling and inflammation/immune response. The KEGG database revealed that exercise regulates 147 metabolic pathways representing molecular interaction networks for Metabolism, Genetic Information Processing, Environmental Information Processing, Cellular Processes, Organismal Systems, and Diseases. These pathways collectively supported the complex regulation of the beneficial effects of exercise on the cartilage. CONCLUSIONS: Overall, the findings highlight that exercise is a robust transcriptional regulator of a wide array of metabolic pathways in healthy cartilage. The major actions of exercise involve ECM biosynthesis/cartilage strengthening and attenuation of inflammatory pathways to provide prophylaxis against onset of arthritic diseases in healthy cartilage.

A multistate framework for the analysis of subsequent injury in sport (M-FASIS).

Physical activity is beneficial for many aspects of health but is associated with a risk of injury. Studies that assess causal risk factors of injury and reinjury provide valuable information to help develop and improve injury prevention programs. However, the underlying assumptions of analytical approaches often used to estimate causal factors in injury and subsequent injury research are often violated. This means that ineffective or even harmful interventions could be proposed because the underlying analyses produced unreliable or invalid causal effect estimates. We describe an adapted version of the multistate framework [multistate framework for the analysis of subsequent injury in sport (M-FASIS)] that makes investigator choices more transparent with respect to outcome and healing time. In addition, M-FASIS incorporates all previous sport injury analytical frameworks and accounts for injuries or conditions that heal or do not heal to 100%, acute and overuse injuries, illnesses, and competing event outcomes.

Sex differences in force attenuation: a clinical assessment of single-leg hop performance on a portable force plate.

OBJECTIVE: Impaired biomechanics and neuromuscular control have been suggested as probable links to female sex bias in the onset of patellofemoral pain syndrome. There are limited objective, clinical measures for assessment of impaired biomechanics and neuromuscular control. The primary objective of this investigation was to examine sex differences in vertical ground reaction force (vGRF) and force loading rate in young athletes performing maximum, repeated vertical single-leg hops (RVSHs). The authors hypothesised that females would demonstrate greater vGRF and force loading rate than males and show interlimb differences in force attenuation. DESIGN: Cross-sectional study. SETTING: Paediatric sports medicine clinic. PARTICIPANTS: 109 Healthy high school, soccer and basketball athletes. ASSESSMENT OF RISK FACTORS: Participants performed RVSHs for 15 seconds on a portable force plate with a sampling rate of 400 Hz (Accupower; AMTI, Watertown, Massachusetts, USA). MAIN OUTCOME MEASUREMENTS: Raw vGRF was filtered with a generalised cross-validation spline using a 50-Hz cutoff frequency and then normalised to potential energy. Force loading rate was calculated by dividing normalised vGRF by time-to-peak force. Group means were compared using analysis of variance. RESULTS: The females demonstrated significantly greater normalised vGRF (p<0.001) and force loading rate (p<0.001) during landing than their male counterparts. Neither sex demonstrated significant interlimb differences in force attenuation (p>0.05). CONCLUSIONS: The female athletes may have altered force attenuation capability during RVSHs as identified by increased vGRF and force loading rate compared with the male athletes. Portable force plates may be potential tools to identify altered force attenuation in clinical settings.

Multiple risk factors related to familial predisposition to anterior cruciate ligament injury: fraternal twin sisters with anterior cruciate ligament ruptures.

OBJECTIVE: A multifactorial combination of predictors may increase anterior cruciate ligament (ACL) injury risk in athletes. The objective of this twin study was to examine these risk factors to identify commonalities in risk factors that predisposed female fraternal twins to ACL injury. METHODS: Female twins in high-risk sports were prospectively measured prior to an injury for neuromuscular control using three-dimensional motion analysis during landing, hamstrings and quadriceps muscular strength on a dynamometer and joint laxity using a modified Beighton-Horan index and a Compu-KT arthrometer. Intraoperative measures of femoral intercondylar notch width were recorded during ACL reconstruction. RESULTS: Abduction angles were increased at one knee in both of the twin sister athletes relative to uninjured controls at initial contact and at maximum displacement during landing. The twin female athletes that went on to ACL injury also demonstrated decreased peak knee flexion motion at both knees than uninjured females during landing. The twin athletes also had increased joint laxity and decreased hamstrings to quadriceps (H/Q) torque ratios compared to controls. Femoral intercondylar notch widths were also below the control mean in the twin siblings. CONCLUSIONS: Prescreened mature female twins that subsequently experienced ACL injury demonstrated multiple potential risk factors including: increased knee abduction angles, decreased knee flexion angles, increased general joint laxity, decreased H/Q ratios and femoral intercondylar notch width.

The anterior cruciate ligament injury controversy: is "valgus collapse" a sex-specific mechanism?

BACKGROUND: Anterior cruciate ligament (ACL) injury is a devastating injury that puts an athlete at high risk of future osteoarthritis. Identification of risk factors and development of ACL prevention programmes likely decrease injury risk. Although studies indicate that sagittal plane biomechanical factors contribute to ACL loading mechanisms, it is unlikely that non-contact ACL injuries occur solely in a sagittal plane. Some authors attempt to ascribe the solely sagittal plane injury mechanism to both female and male ACL injuries and rebuff the concept that knee "valgus" is associated with isolated ACL injury. Prospective studies that utilise coupled biomechanical and epidemiological approaches demonstrated that frontal knee motions and torques are strong predictors of future non-contact ACL injury risk in female athletes. Video analysis studies also indicate a frontal plane "valgus collapse" mechanism of injury in women. As load sharing between knee ligaments is complex, frontal as well as sagittal and transverse plane loading mechanisms likely contribute to non-contact ACL injury. The purpose of this review is to summarise existing evidence regarding ACL injury mechanisms and to propose that sex-specific mechanisms of ACL injury may occur, with women sustaining injuries by a predominantly "valgus collapse" mechanism. CONCLUSION: Prevention programmes and interventions that only target high-risk sagittal plane landing mechanics, especially in the female athlete, are likely to be less effective in ameliorating important frontal and transverse plane contributions to ACL injury mechanisms and could seriously hamper ACL injury prevention efforts. Programmes that target the reduction of high-risk valgus and sagittal plane movements will probably prove to be superior for ACL injury prevention.

Prediction and prevention of musculoskeletal injury: a paradigm shift in methodology.

Traditional methods employed to study musculoskeletal injury mechanisms and joint biomechanics utilise in vivo or in vitro techniques. The advent of new technology and improved methods has also given rise to in silico (computer modelling) techniques. Under the current research paradigm, in vivo, in vitro and in silico methods independently provide information regarding the mechanisms and prevention of musculoskeletal injury. However, individually, each of these methods has multiple, inherent limitations and is likely to provide incomplete answers about multifactorial, complex injury conditions. The purpose of this treatise is to review current methods used to study, understand, and prevent musculoskeletal injury and to develop new conceptual-methodological frameworks that may help create a paradigm shift in musculoskeletal injury prevention research. We term the fusion of these three techniques in simulacra amalgama, or simply in sim, meaning a "union of models done on the likeness of phenomena." Anterior cruciate ligament (ACL) injury will be employed as a model example for the utility and applicability of the proposed, synthesised approach. Shifting the current experimental paradigm to incorporate a multifaceted, multidisciplinary, integration of in vivo, in vitro and in silico methods into the proposed in sim approaches may provide a platform for a more comprehensive understanding of the relationships between complex joint biomechanics and observed injury mechanisms.

Video analysis of trunk and knee motion during non-contact anterior cruciate ligament injury in female athletes: lateral trunk and knee abduction motion are combined components of the injury mechanism.

BACKGROUND: The combined positioning of the trunk and knee in the coronal and sagittal planes during non-contact anterior cruciate ligament (ACL) injury has not been previously reported. HYPOTHESIS: During ACL injury female athletes demonstrate greater lateral trunk and knee abduction angles than ACL-injured male athletes and uninjured female athletes. DESIGN: Cross-section control-cohort design. METHODS: Analyses of still captures from 23 coronal (10 female and 7 male ACL-injured players and 6 female controls) or 28 sagittal plane videos performing similar landing and cutting tasks. Significance was set at p < or = 0.05. RESULTS: Lateral trunk and knee abduction angles were higher in female compared to male athletes during ACL injury (p < or = 0.05) and trended toward being greater than female controls (p = 0.16, 0.13, respectively). Female ACL-injured athletes showed less forward trunk lean than female controls (mean (SD) initial contact (IC): 1.6 (9.3) degrees vs 14.0 (7.3) degrees, p < or = 0.01). CONCLUSION: Female athletes landed with greater lateral trunk motion and knee abduction during ACL injury than did male athletes or control females during similar landing and cutting tasks. CLINICAL RELEVANCE: Lateral trunk and knee abduction motion are important components of the ACL injury mechanism in female athletes as observed from video evidence of ACL injury.

A pilot study to determine the effect of trunk and hip focused neuromuscular training on hip and knee isokinetic strength.

OBJECTIVE: The objective was to determine the effect of trunk focused neuromuscular training (TNMT) on hip and knee strength. The hypothesis was that TNMT would increase standing isokinetic hip abduction, but not knee flexion/extension, strength. METHODS: 21 high-school female volleyball players (14 TMNT, mean age 15.4 (1.4) years, weight 170.5 (5.0) cm, height 64.1 (8.5) kg and 7 controls, mean age 16.0 (1.7) years, height 173.4 (10.0) cm, weight 63.9 (5.3) kg; p>0.05) were recruited to participate in this study. The 14 TNMT subjects participated in a TNMT protocol (twice weekly) over a 10 week period in addition to their standard once-weekly off-season strength training. Standing isokinetic hip abduction strength and seated knee flexion/extension strength were measured before and after TNMT. RESULTS: A significant interaction of group and time was observed. The TNMT group increased isokinetic hip abduction strength approximately 15% (13.5% in the dominant leg: mean (SD) 46.6 (10.1) to 52.9 (11.4) foot-pounds and 17.1% in the non-dominant leg: 46.1 (10.4) to 54.0 (10.7) foot-pounds; p = 0.01). There was no difference in the control group in pre-test versus post-test measures. Post-test results also indicated no effect of TNMT on isokinetic knee extension (p = 0.57) or knee flexion (p = 0.57) strength. CONCLUSIONS: Ten weeks of TNMT increased standing hip abduction strength in female athletes. Increased hip abduction strength and recruitment may improve the ability of female athletes to increase control of lower limb alignment and decrease knee loads resulting from increased trunk displacement during sports activities.

The effects of age and skill level on knee musculature co-contraction during functional activities: a systematic review.

OBJECTIVES: To systematically review the current literature that relates the effects of age and skill level to motor control patterns of knee musculature co-contraction during functional movements. METHODS: A search of electronic databases was performed with the search terms specifying co-contraction (cocontract*, co-contract*, coactive* or co-activ*). The search was focused on the effects age and/or skill level and were limited by the keywords of age or skill level (skill*) or experience (experi*). RESULTS: The search yielded a total of six peer-reviewed manuscripts that met the search criteria and were included in the review. CONCLUSIONS: The relationship between adequate dynamic joint stability and efficient movement patterns are complex. Co-contraction related to age and skill development varies among studies due to technical and practical considerations. Adequate antagonistic co-contraction of hamstring musculature seems to be a component of all functional movements, possibly maintain dynamic knee stability and protect against excessive joint loads. Future investigations that further delineate the appropriate lower extremity agonist and antagonist relationships during dynamic tasks may help elucidate injury risk mechanisms in specific populations.

Non-contact ACL injuries in female athletes: an International Olympic Committee current concepts statement.

The incidence of anterior cruciate ligament (ACL) injury remains high in young athletes. Because female athletes have a much higher incidence of ACL injuries in sports such as basketball and team handball than male athletes, the IOC Medical Commission invited a multidisciplinary group of ACL expert clinicians and scientists to (1) review current evidence including data from the new Scandinavian ACL registries; (2) critically evaluate high-quality studies of injury mechanics; (3) consider the key elements of successful prevention programmes; (4) summarise clinical management including surgery and conservative management; and (5) identify areas for further research. Risk factors for female athletes suffering ACL injury include: (1) being in the preovulatory phase of the menstrual cycle compared with the postovulatory phase; (2) having decreased intercondylar notch width on plain radiography; and (3) developing increased knee abduction moment (a valgus intersegmental torque) during impact on landing. Well-designed injury prevention programmes reduce the risk of ACL for athletes, particularly women. These programmes attempt to alter dynamic loading of the tibiofemoral joint through neuromuscular and proprioceptive training. They emphasise proper landing and cutting techniques. This includes landing softly on the forefoot and rolling back to the rearfoot, engaging knee and hip flexion and, where possible, landing on two feet. Players are trained to avoid excessive dynamic valgus of the knee and to focus on the "knee over toe position" when cutting.

A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy can be caused by mutations in genes encoding sarcomeric proteins, including the cardiac isoform of myosin binding protein C (MyBP-C), and multiple mutations which cause truncated forms of the protein to be made are linked to the disease. We have created transgenic mice in which varying amounts of a mutated MyBP-C, lacking the myosin and titin binding domains, are expressed in the heart. The transgenically encoded, truncated protein is stable but is not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the pCa2+-force curve and, importantly, their power output was reduced. Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, resulting in a striking pattern of sarcomere disorganization and dysgenesis.

Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice.

The different functions of the ventricular- and atrial-specific essential myosin light chains are unknown. Using transgenesis, cardiac-specific overexpression of proteins can be accomplished. The transgenic paradigm is more useful than originally expected, in that the mammalian heart rigorously controls sarcomeric protein stoichiometries. In a clinical subpopulation suffering from heart disease caused by congenital malformations of the outflow tract, an ELC1v-->ELC1a isoform shift correlated with increases in cross-bridge cycling kinetics as measured in skinned fibers derived from the diseased muscle. We have used transgenesis to replace the ventricular isoform of the essential myosin light chain with the atrial isoform. The ELC1v--> ELC1a shift in the ventricle resulted in similar functional alterations. Unloaded velocities as measured by the ability of the myosin to translocate actin filaments in the in vitro motility assay were significantly increased as a result of the isoform substitution. Unloaded shortening velocity was also increased in skinned muscle fibers, and at the whole organ level, both contractility and relaxation were significantly increased. This increase in cardiac function occurred in the absence of a hypertrophic response. Thus, ELC1a expression in the ventricle appears to be advantageous to the heart, resulting in increased cardiac function.

Altered focal adhesion regulation correlates with cardiomyopathy in mice expressing constitutively active rac1.

The ras family of small GTP-binding proteins exerts powerful effects upon cell structure and function. One member of this family, rac, induces actin cytoskeletal reorganization in nonmuscle cells and hypertrophic changes in cultured cardiomyocytes. To examine the effect of rac1 activation upon cardiac structure and function, transgenic mice were created that express constitutively activated rac1 specifically in the myocardium. Transgenic rac1 protein was expressed at levels comparable to endogenous rac levels, with activation of the rac1 signaling pathway resulting in two distinct cardiomyopathic phenotypes: a lethal dilated phenotype associated with neonatal activation of the transgene and a transient cardiac hypertrophy seen among juvenile mice that resolved with age. Neither phenotype showed myofibril disarray and hypertrophic hearts were hypercontractilein working heart analyses. The rac1 target p21-activated kinase translocated from a cytosolic to a cytoskeletal distribution, suggesting that rac1 activation was inducing focal adhesion reorganization. Corroborating results showed altered localizations of src in dilated cardiomyopathy and paxillin in both cardiomyopathic phenotypes. This study, the first examination of rac1-mediated cardiac effects in vivo, demonstrates that dilation and hypertrophy can share a common molecular origin and presents evidence that both timing and concurrent signaling from multiple pathways can influence cardiac remodeling.

A truncated cardiac troponin T molecule in transgenic mice suggests multiple cellular mechanisms for familial hypertrophic cardiomyopathy.

Mutations in multiple cardiac sarcomeric proteins including myosin heavy chain (MyHC) and cardiac troponin T (cTnT) cause a dominant genetic heart disease, familial hypertrophic cardiomyopathy (FHC). Patients with mutations in these two genes have quite distinct clinical characteristics. Those with MyHC mutations demonstrate more significant and uniform cardiac hypertrophy and a variable frequency of sudden death. Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age. To understand the basis for these distinctions and to study the pathogenesis of the disease, we have created transgenic mice expressing a truncated mouse cTnT allele analogous to one found in FHC patients. Mice expressing truncated cTnT at low (< 5%) levels develop cardiomyopathy and their hearts are significantly smaller (18-27%) than wild type. These animals also exhibit significant diastolic dysfunction and milder systolic dysfunction. Animals that express higher levels of transgene protein die within 24 h of birth. Transgenic mouse hearts demonstrate myocellular disarray and have a reduced number of cardiac myocytes that are smaller in size. These studies suggest that multiple cellular mechanisms result in the human disease, which is generally characterized by mild hypertrophy, but, also, frequent sudden death.

Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice.

Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-MyHC-RAR animals, where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventricular chamber dilation and left atrial thrombosis; the incidence and severity of these lesions increased with increasing copy number. Transcript analyses showed that molecular markers of hypertrophy, alpha-skeletal actin, atrial natriuretic factor and beta-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as well as in vivo, by transthoracic M-mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/ or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction.

Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy.

Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC). Patients with cTnT mutations generally exhibit mild or no ventricular hypertrophy, yet demonstrate a high frequency of early sudden death. To understand the functional basis of these phenotypes, we created transgenic mouse lines expressing 30%, 67%, and 92% of their total cTnT as a missense (R92Q) allele analogous to one found in FHC. Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type. In striking contrast to truncation mice, however, the R92Q hearts demonstrate significant induction of atrial natriuretic factor and beta-myosin heavy chain transcripts, interstitial fibrosis, and mitochondrial pathology. Isolated cardiac myocytes from R92Q mice have increased basal sarcomeric activation, impaired relaxation, and shorter sarcomere lengths. Isolated working heart data are consistent, showing hypercontractility and diastolic dysfunction, both of which are common findings in patients with FHC. These mice represent the first disease model to exhibit hypercontractility, as well as a unique model system for exploring the cellular pathogenesis of FHC. The distinct phenotypes of mice with different TnT alleles suggest that the clinical heterogeneity of FHC is at least partially due to allele-specific mechanisms.

Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart.

The alpha-myosin heavy chain (alpha-MyHC) is the major contractile protein expressed in the myocardium of adult mice. We have produced mice carrying a null mutation of alpha-MyHC by homologous recombination in murine ES cells. Homozygous null animals die between 11 and 12 d in utero of gross heart defects, while alpha-MyHC+/- heterozygotes survive and appear externally normal. The presence of a single functional alpha-MyHC+ allele in heterozygous animals results in reduced levels of the transcript and protein as well as fibrosis and alterations in sarcomeric structure. Examination of heart function using a working heart preparation revealed severe impairment of both contractility and relaxation in a subset of the alpha-MyHC+/- animals. Thus, two alpha-MyHC+ alleles are necessary for normal cardiac development, and hemizygosity for the normal allele can result in altered cardiac function.

Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice.

Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.

Transgenic modeling of a cardiac troponin I mutation linked to familial hypertrophic cardiomyopathy.

Multiple mutations in cardiac troponin I (cTnI) have been associated with familial hypertrophic cardiomyopathy. Two mutations are located in the cTnI inhibitory domain, a highly negatively charged region that alternately binds to either actin or troponin C, depending on the intracellular concentration of calcium. This region is critical to the inhibition of actin-myosin crossbridge formation when intracellular calcium is low. We modeled one of the inhibitory domain mutations, arginine145-->glycine (TnI(146Gly) in the mouse sequence), by cardiac-specific expression of the mutated protein in transgenic mice. Multiple lines were generated with varying degrees of expression to establish a dose relationship; the severity of phenotype could be correlated directly with transgene expression levels. Transgenic mice overexpressing wild-type cTnI were generated as controls and analyzed in parallel with the TnI(146Gly) animals. The control mice showed no abnormalities, indicating that the phenotype of TnI(146Gly) was not simply an artifact of transgenesis. In contrast, TnI(146Gly) mice showed cardiomyocyte disarray and interstitial fibrosis and suffered premature death. The functional alterations that seem to be responsible for the development of cardiac disease include increased skinned fiber sensitivity to calcium and, at the whole organ level, hypercontractility with diastolic dysfunction. Severely affected lines develop a pathology similar to human familial hypertrophic cardiomyopathy but within a dramatically shortened time frame. These data establish the causality of this mutation for cardiac disease, provide an animal model for understanding the resultant pathogenic structure-function relationships, and highlight the differences in phenotype severity of the troponin mutations between human and mouse hearts.