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Gary C. Sieck - One of the best experts on this subject based on the ideXlab platform.

  • Impact of congenital Diaphragmatic hernia on Diaphragm Muscle function in neonatal rats.
    Journal of applied physiology (Bethesda Md. : 1985), 2021
    Co-Authors: Matthew J. Fogarty, Elizabeth Ann L. Enninga, Eniola R. Ibirogba, Rodrigo Ruano, Gary C. Sieck
    Abstract:

    Congenital Diaphragmatic hernia (CDH) is characterized by incomplete partitioning of the thoracic and abdominal cavities by the Diaphragm Muscle (DIAm). The resulting in utero invasion of the abdom...

  • Diaphragm Muscle fatigue resistance does not increase with age
    Revista Cubana de Investigaciones Biomedicas, 2020
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Gary C. Sieck
    Abstract:

    Introduction: The Diaphragm Muscle (DIAm) contains a mixed motor units population, with FInt and FF units (comprising type IIx and/or IIb Muscle fibers) vulnerable to sarcopenia - age-associated reductions of specific force and cross-sectional area (CSA). Fatigue-resistant S and FR units (comprising type I and IIa fibers) are relatively spared. There is controversy as to whether aging confers an enhanced resistance to DIAm fatigue, with interpretations relying on relative measurements of force. Objective: To quantify differences in fatigue resistance between young (6-months) and old (24 months) Fischer 344 rats, taking into account maximum specific forces. Material and Methods: We assessed the loss of DIAm force in young and old Fischer 344 rats of both sexes at 10, 40 and 75 Hz stimulation in 330 ms duration trains repeated each s (33% duty cycle) across a 2 min period. Results: Although the initial specific force of the DIAm was lower in older rats across all stimulation frequencies, the final residual DIAm specific force after 2 min of stimulation was the same (~5 N/cm 2 ) at all ages. These relative values gave the misconception of an improved fatigue resistance, especially at 40 and 75 Hz. We also found that aging is associated with an increase in the relative contributions of type I and IIa fiber CSA to DIAm mass with decreased contributions of type IIx and/or IIb fibers. When these changing contributions are factored into a fiber type-specific model of DIAm force generation, we found that ventilatory behaviors require activation of only type I and IIa fibers, regardless of age or fatigue. By contrast, the model predicts that aging impairs the ability of the DIAm to effectively perform expulsive manoeuvres, even in the non-fatigued condition. Conclusions: Relative fatigue measurements are not indicative of improved fatigue resistance in aging and are an artifact of reduced initial specific force contributions from FInt and FF units. These results are consistent with previous studies showing the relative vulnerability of FInt and FF units and conserved ventilatory behaviors in aging DIAm. Keywords: Diaphragm Muscle, Muscle fatigue resistance, age. rats, ventilatory behaviors,

  • aging reduces succinate dehydrogenase activity in rat type iix iib Diaphragm Muscle fibers
    Journal of Applied Physiology, 2020
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Natalia Marin Mathieu, Gary C. Sieck
    Abstract:

    We examined the oxidative capacity as measured by maximum succinate dehydrogenase activity in older (18 or 24 mo old) Fischer 344 rat Diaphragm Muscle (DIAm) compared with young rats (6 mo old). In...

  • Diaphragm Muscle Adaptations in Health and Disease
    Drug discovery today. Disease models, 2019
    Co-Authors: Matthew J. Fogarty, Gary C. Sieck
    Abstract:

    Breathing is achieved without thought despite being controlled by a complex neural network. The Diaphragm is the predominant Muscle responsible for force/pressure generation during breathing, but it is also involved in other non-ventilatory expulsive behaviors. This review considers alterations in Diaphragm Muscle fiber types and the neural control of the Diaphragm across our lifespan and in various disease conditions.

  • Impact of sarcopenia on Diaphragm Muscle fatigue.
    Experimental physiology, 2019
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Gary C. Sieck
    Abstract:

    NEW FINDINGS What is the central question of this study? Is the residual force generated by the Diaphragm Muscle after repeated activation reduced with sarcopenia, and is the residual force generated after fatiguing activation sufficient to sustain ventilatory behaviours of Diaphragm Muscle in young and old rats? What is the main finding and its importance? After Diaphragm Muscle fatigue, the residual specific force after 120 s of repeated stimulation was unaffected by ageing and was sufficient to accomplish ventilatory behaviours, but not expulsive manoeuvres (e.g. coughing). The inability to perform expulsive behaviours might underlie the increased susceptibility of older individuals to respiratory tract infections. ABSTRACT Type IIx and/or IIb Diaphragm Muscle (DIAm) fibres make up more fatigable motor units that are more vulnerable to sarcopenia, i.e. age-associated reductions of specific force and cross-sectional area. In contrast, type I and IIa DIAm fibres form fatigue-resistant motor units that are relatively unchanged with age. The fatigue resistance of the DIAm is assessed by normalizing the residual force generated after a period of repeated supramaximal stimulation (e.g. 120 s) to the initial maximal force. Given that sarcopenia primarily affects more fatigable DIAm motor units, apparent fatigue resistance improves with ageing. However, the central question is whether there is an ageing-related difference in the residual force generated by the DIAm after repeated stimulation and whether this force is sufficient to sustain ventilatory behaviours of DIAm. In 6- and 24-month-old Fischer 344 rats, we assessed the loss of ex vivo DIAm force throughout 120 s of repeated supramaximal stimulation at 10, 40 and 75 Hz. We found that relative fatigue resistance improved in older rats at 40 and 75 Hz stimulation. Across all stimulation frequencies, DIAm residual force was unchanged with age (∼5 N cm-2 ). We conclude that ageing increases the relative contribution of type I and IIa fibres to DIAm force, with decreased contributions of type IIx and/or IIb fibres. The residual force generated by the DIAm after repeated stimulation is sufficient to accomplish ventilatory behaviours, regardless of age.

Jian Ping Jin - One of the best experts on this subject based on the ideXlab platform.

  • deletion of a genomic segment containing the cardiac troponin i gene knocks down expression of the slow troponin t gene and impairs fatigue tolerance of Diaphragm Muscle
    Journal of Biological Chemistry, 2009
    Co-Authors: Hanzhong Feng, Bin Wei, Jian Ping Jin
    Abstract:

    The loss of slow skeletal Muscle troponin T (TnT) results in a recessive nemaline myopathy in the Amish featured with lethal respiratory failure. The genes encoding slow TnT and cardiac troponin I (TnI) are closely linked. Ex vivo promoter analysis suggested that the 5'-enhancer region of the slow TnT gene overlaps with the structure of the upstream cardiac TnI gene. Using transgenic expression of exogenous cardiac TnI to rescue the postnatal lethality of a mouse line in which the entire cardiac TnI gene was deleted, we investigated the effect of enhancer deletion on slow TnT gene expression in vivo and functional consequences. The levels of slow TnT mRNA and protein were significantly reduced in the Diaphragm Muscle of adult double transgenic mice. The slow TnT-deficient (ssTnT-KD) Diaphragm Muscle exhibited atrophy and decreased ratios of slow versus fast isoforms of TnT, TnI, and myosin. Consistent with the changes toward more fast myofilament contents, ssTnT-KD Diaphragm Muscle required stimulation at higher frequency for optimal tetanic force production. The ssTnT-KD Diaphragm Muscle also exhibited significantly reduced fatigue tolerance, showing faster and more declines of force with slower and less recovery from fatigue as compared with the wild type controls. The natural switch to more slow fiber contents during aging was partially blunted in the ssTnT-KD skeletal Muscle. The data demonstrated a critical role of slow TnT in Diaphragm function and in the pathogenesis and pathophysiology of Amish nemaline myopathy.

  • Decreased Fatigue Tolerance In Diaphragm Muscle Of Slow Troponin T Knockdown Mice
    Biophysical Journal, 2009
    Co-Authors: Hanzhong Feng, Bin Wei, Jian Ping Jin
    Abstract:

    The loss of slow skeletal Muscle troponin T (TnT) results in a severe type of nemaline myopathy in the Amish (ANM). The genes encoding TnT and troponin I (TnI) are closely linked in pairs in which the 5′-enhancer region of the slow TnT gene overlaps with the cardiac TnI gene. In a mouse line with the entire cardiac TnI gene deleted, a partial destruction of the slow TnT gene promoter produces a knockdown effect. By crossing with transgenic mouse lines that over-express a core structure of cardiac TnI (cTnI-ND) under the control of cloned alpha-MHC promoter, we rescued the postnatal lethality of the cardiac TnI gene-deleted mice with no detrimental cardiac phenotypes or leaking expression in non-cardiac tissues. The double transgenic mice exhibited decreased expression of slow TnT mRNA and protein in adult Diaphragm Muscle. Functional analysis of isolated Muscle strips showed that the slow TnT deficient (sTnT-KD) Diaphragm had significantly decreased fatigue tolerance evident by the faster decrease in force and slower rate of recovery as compared with that in wild type controls. As a consequence of slow TnT deficiency, the sTnT-KD Diaphragm Muscle contained a higher proportion of fast TnT, decreased slow TnI with increased fast TnI, and decreased type I myosin with increased type II myosin. Consistent with the switch toward fast myofilament contents, the sTnT-KD Diaphragm Muscle produced higher specific tension in twitch and tetanic contractions as well as shorter time to develop peak tension in twitch contractions. The decreased fatigue tolerance of sTnT-KD Diaphragm Muscle explains the terminal respiratory failure seen in virtually all ANM patients and this double transgenic mouse model provides a useful experimental system to study the pathogenesis and treatment of ANM.

Carlos B. Mantilla - One of the best experts on this subject based on the ideXlab platform.

  • Diaphragm Muscle fatigue resistance does not increase with age
    Revista Cubana de Investigaciones Biomedicas, 2020
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Gary C. Sieck
    Abstract:

    Introduction: The Diaphragm Muscle (DIAm) contains a mixed motor units population, with FInt and FF units (comprising type IIx and/or IIb Muscle fibers) vulnerable to sarcopenia - age-associated reductions of specific force and cross-sectional area (CSA). Fatigue-resistant S and FR units (comprising type I and IIa fibers) are relatively spared. There is controversy as to whether aging confers an enhanced resistance to DIAm fatigue, with interpretations relying on relative measurements of force. Objective: To quantify differences in fatigue resistance between young (6-months) and old (24 months) Fischer 344 rats, taking into account maximum specific forces. Material and Methods: We assessed the loss of DIAm force in young and old Fischer 344 rats of both sexes at 10, 40 and 75 Hz stimulation in 330 ms duration trains repeated each s (33% duty cycle) across a 2 min period. Results: Although the initial specific force of the DIAm was lower in older rats across all stimulation frequencies, the final residual DIAm specific force after 2 min of stimulation was the same (~5 N/cm 2 ) at all ages. These relative values gave the misconception of an improved fatigue resistance, especially at 40 and 75 Hz. We also found that aging is associated with an increase in the relative contributions of type I and IIa fiber CSA to DIAm mass with decreased contributions of type IIx and/or IIb fibers. When these changing contributions are factored into a fiber type-specific model of DIAm force generation, we found that ventilatory behaviors require activation of only type I and IIa fibers, regardless of age or fatigue. By contrast, the model predicts that aging impairs the ability of the DIAm to effectively perform expulsive manoeuvres, even in the non-fatigued condition. Conclusions: Relative fatigue measurements are not indicative of improved fatigue resistance in aging and are an artifact of reduced initial specific force contributions from FInt and FF units. These results are consistent with previous studies showing the relative vulnerability of FInt and FF units and conserved ventilatory behaviors in aging DIAm. Keywords: Diaphragm Muscle, Muscle fatigue resistance, age. rats, ventilatory behaviors,

  • aging reduces succinate dehydrogenase activity in rat type iix iib Diaphragm Muscle fibers
    Journal of Applied Physiology, 2020
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Natalia Marin Mathieu, Gary C. Sieck
    Abstract:

    We examined the oxidative capacity as measured by maximum succinate dehydrogenase activity in older (18 or 24 mo old) Fischer 344 rat Diaphragm Muscle (DIAm) compared with young rats (6 mo old). In...

  • Impact of sarcopenia on Diaphragm Muscle fatigue.
    Experimental physiology, 2019
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Gary C. Sieck
    Abstract:

    NEW FINDINGS What is the central question of this study? Is the residual force generated by the Diaphragm Muscle after repeated activation reduced with sarcopenia, and is the residual force generated after fatiguing activation sufficient to sustain ventilatory behaviours of Diaphragm Muscle in young and old rats? What is the main finding and its importance? After Diaphragm Muscle fatigue, the residual specific force after 120 s of repeated stimulation was unaffected by ageing and was sufficient to accomplish ventilatory behaviours, but not expulsive manoeuvres (e.g. coughing). The inability to perform expulsive behaviours might underlie the increased susceptibility of older individuals to respiratory tract infections. ABSTRACT Type IIx and/or IIb Diaphragm Muscle (DIAm) fibres make up more fatigable motor units that are more vulnerable to sarcopenia, i.e. age-associated reductions of specific force and cross-sectional area. In contrast, type I and IIa DIAm fibres form fatigue-resistant motor units that are relatively unchanged with age. The fatigue resistance of the DIAm is assessed by normalizing the residual force generated after a period of repeated supramaximal stimulation (e.g. 120 s) to the initial maximal force. Given that sarcopenia primarily affects more fatigable DIAm motor units, apparent fatigue resistance improves with ageing. However, the central question is whether there is an ageing-related difference in the residual force generated by the DIAm after repeated stimulation and whether this force is sufficient to sustain ventilatory behaviours of DIAm. In 6- and 24-month-old Fischer 344 rats, we assessed the loss of ex vivo DIAm force throughout 120 s of repeated supramaximal stimulation at 10, 40 and 75 Hz. We found that relative fatigue resistance improved in older rats at 40 and 75 Hz stimulation. Across all stimulation frequencies, DIAm residual force was unchanged with age (∼5 N cm-2 ). We conclude that ageing increases the relative contribution of type I and IIa fibres to DIAm force, with decreased contributions of type IIx and/or IIb fibres. The residual force generated by the DIAm after repeated stimulation is sufficient to accomplish ventilatory behaviours, regardless of age.

  • Phrenic motoneuron structural plasticity across models of Diaphragm Muscle paralysis.
    The Journal of comparative neurology, 2018
    Co-Authors: Carlos B. Mantilla, Wen Zhi Zhan, Heather M. Gransee, Y. S. Prakash, Gary C. Sieck
    Abstract:

    Structural plasticity in motoneurons may be influenced by activation history and motoneuron-Muscle fiber interactions. The goal of this study was to examine the morphological adaptations of phrenic motoneurons following imposed motoneuron inactivity while controlling for Diaphragm Muscle inactivity. Well-characterized rat models were used including unilateral C2 spinal hemisection (SH; ipsilateral phrenic motoneurons and Diaphragm Muscle are inactive) and tetrodotoxin phrenic nerve blockade (TTX; ipsilateral Diaphragm Muscle is paralyzed while phrenic motoneuron activity is preserved). We hypothesized that inactivity of phrenic motoneurons would result in a decrease in motoneuron size, consistent with a homeostatic increase in excitability. Phrenic motoneurons were retrogradely labeled by ipsilateral Diaphragm Muscle injection of fluorescent dextrans or cholera toxin subunit B. Following 2 weeks of Diaphragm Muscle paralysis, morphological parameters of labeled ipsilateral phrenic motoneurons were assessed quantitatively using fluorescence confocal microscopy. Compared to controls, phrenic motoneuron somal volumes and surface areas decreased with SH, but increased with TTX. Total phrenic motoneuron surface area was unchanged by SH, but increased with TTX. Dendritic surface area was estimated from primary dendrite diameter using a power equation obtained from three-dimensional reconstructed phrenic motoneurons. Estimated dendritic surface area was not significantly different between control and SH, but increased with TTX. Similarly, TTX significantly increased total phrenic motoneuron surface area. These results suggest that ipsilateral phrenic motoneuron morphological adaptations are consistent with a normalization of motoneuron excitability following prolonged alterations in motoneuron activity. Phrenic motoneuron structural plasticity is likely more dependent on motoneuron activity (or descending input) than Muscle fiber activity.

  • Breathing: Motor Control of Diaphragm Muscle.
    Physiology (Bethesda Md.), 2018
    Co-Authors: Matthew J. Fogarty, Carlos B. Mantilla, Gary C. Sieck
    Abstract:

    Breathing occurs without thought but is controlled by a complex neural network with a final output of phrenic motor neurons activating Diaphragm Muscle fibers (i.e., motor units). This review considers Diaphragm motor unit organization and how they are controlled during breathing as well as during expulsive behaviors.

Luc E. Gosselin - One of the best experts on this subject based on the ideXlab platform.

  • Pentoxifylline fails to attenuate fibrosis in dystrophic (mdx) Diaphragm Muscle.
    Muscle & nerve, 2006
    Co-Authors: Luc E. Gosselin, Jacqueline E. Williams
    Abstract:

    Fibrosis is a common pathological feature observed in Muscle from patients with Duchenne muscular dystrophy and in mdx Diaphragm. The purpose of this study was to determine whether pentoxifylline (PTX) treatment for 4 weeks (16 mg/kg/day) could significantly attenuate the process of fibrosis in Diaphragm Muscle from mdx mice. PTX treatment had no impact on in vitro Diaphragm Muscle contractile function. In addition, Diaphragm Muscle hydroxyproline concentration and the level of type I and III collagen and TGF-beta1 mRNA were unaffected by PTX treatment. These findings do not support the use of PTX as an antifibrotic drug for the treatment of muscular dystrophy.

  • impact of prednisone on tgf β1 and collagen in Diaphragm Muscle from mdx mice
    Muscle & Nerve, 2001
    Co-Authors: James V. Hartel, Michael S. Hudecki, Cathy M. Pollina, J A Granchelli, Luc E. Gosselin
    Abstract:

    The purpose of this study was to assess the impact of prednisone treatment for 8 weeks on the level of transforming growth factor-beta 1 (TGF-beta1), hydroxyproline (HYP) concentrations, and level of the mature, nonreducible collagen cross-link hydroxylysylpyridinoline (HP) in Diaphragm Muscle from 12-week-old mdx mice. Diaphragm Muscle from untreated mdx mice had a significantly higher level of TGF-beta1, HYP, and HP cross-link compared with normal C57BL/10J (control) mice. Prednisone treatment significantly reduced the level of TGF-beta1 and HYP in Diaphragm from mdx mice to values similar to control mice, but resulted in a higher level of the HP cross-link compared with untreated mdx mice. These findings indicate that short-term treatment of mdx mice with prednisone can attenuate the fibrotic response in Diaphragm Muscle, possibly by mediating the level of TGF-beta. Although prednisone was beneficial in preventing collagen accumulation, it resulted in a higher level of the HP cross-link, presumably by decreasing collagen turnover

  • Impact of prednisone on TGF‐β1 and collagen in Diaphragm Muscle from mdx mice
    Muscle & nerve, 2001
    Co-Authors: James V. Hartel, Michael S. Hudecki, Cathy M. Pollina, Luc E. Gosselin
    Abstract:

    The purpose of this study was to assess the impact of prednisone treatment for 8 weeks on the level of transforming growth factor-beta 1 (TGF-beta1), hydroxyproline (HYP) concentrations, and level of the mature, nonreducible collagen cross-link hydroxylysylpyridinoline (HP) in Diaphragm Muscle from 12-week-old mdx mice. Diaphragm Muscle from untreated mdx mice had a significantly higher level of TGF-beta1, HYP, and HP cross-link compared with normal C57BL/10J (control) mice. Prednisone treatment significantly reduced the level of TGF-beta1 and HYP in Diaphragm from mdx mice to values similar to control mice, but resulted in a higher level of the HP cross-link compared with untreated mdx mice. These findings indicate that short-term treatment of mdx mice with prednisone can attenuate the fibrotic response in Diaphragm Muscle, possibly by mediating the level of TGF-beta. Although prednisone was beneficial in preventing collagen accumulation, it resulted in a higher level of the HP cross-link, presumably by decreasing collagen turnover

  • Hypothyroid-mediated changes in adult rat Diaphragm Muscle contractile properties and MHC isoform expression
    Journal of applied physiology (Bethesda Md. : 1985), 1996
    Co-Authors: Luc E. Gosselin, Wen Zhi Zhan, Gary C. Sieck
    Abstract:

    The purpose of the present study was to examine the effect of acute hypothyroidism on myosin heavy chain (MHC) isoform composition and contractile properties in the adult rat Diaphragm Muscle. Hypothyroidism was induced by the addition of propylthiouracil (0.05%) in the drinking water for a period of 3 wk. MHC isoform composition of control and hypothyroid Diaphragm Muscles was assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In vitro isometric contractile properties of midcostal Diaphragm Muscle segements were measured at 26 degrees C, whereas the maximal unloaded shortening velocity was measured at 15 degrees C with the "slack test" method. Serum triiodothyronine and thyroxine values were significantly lower in the hypothyroid compared with the control group. A small but significant increase in the percentage of slow MHC isoform in the Diaphragm was observed with acute hypothyroidism, whereas the percentage of the fast MHC isoforms (2A, 2X, and 2B) did not significantly differ between groups. Peak twitch force did not differ between groups. However, twitch contraction and half-relaxation times were significantly prolonged in the hypothyroid group compared with control. Maximal specific force was reduced in the hypothyroid compared with the control group, averaging 15.7 and 19.8 N/cm2, respectively (P < 0.05). The maximal unloaded shortening velocity averaged 4.3 and 8.2 Muscle lengths/s in the hypothyroid and control groups, respectively (P < 0.05). We conclude that acute hypothyroidism results in alterations in adult Diaphragm Muscle contractile properties that cannot be attributed solely to changes in MHC isoform composition.

Hanzhong Feng - One of the best experts on this subject based on the ideXlab platform.

  • deletion of a genomic segment containing the cardiac troponin i gene knocks down expression of the slow troponin t gene and impairs fatigue tolerance of Diaphragm Muscle
    Journal of Biological Chemistry, 2009
    Co-Authors: Hanzhong Feng, Bin Wei, Jian Ping Jin
    Abstract:

    The loss of slow skeletal Muscle troponin T (TnT) results in a recessive nemaline myopathy in the Amish featured with lethal respiratory failure. The genes encoding slow TnT and cardiac troponin I (TnI) are closely linked. Ex vivo promoter analysis suggested that the 5'-enhancer region of the slow TnT gene overlaps with the structure of the upstream cardiac TnI gene. Using transgenic expression of exogenous cardiac TnI to rescue the postnatal lethality of a mouse line in which the entire cardiac TnI gene was deleted, we investigated the effect of enhancer deletion on slow TnT gene expression in vivo and functional consequences. The levels of slow TnT mRNA and protein were significantly reduced in the Diaphragm Muscle of adult double transgenic mice. The slow TnT-deficient (ssTnT-KD) Diaphragm Muscle exhibited atrophy and decreased ratios of slow versus fast isoforms of TnT, TnI, and myosin. Consistent with the changes toward more fast myofilament contents, ssTnT-KD Diaphragm Muscle required stimulation at higher frequency for optimal tetanic force production. The ssTnT-KD Diaphragm Muscle also exhibited significantly reduced fatigue tolerance, showing faster and more declines of force with slower and less recovery from fatigue as compared with the wild type controls. The natural switch to more slow fiber contents during aging was partially blunted in the ssTnT-KD skeletal Muscle. The data demonstrated a critical role of slow TnT in Diaphragm function and in the pathogenesis and pathophysiology of Amish nemaline myopathy.

  • Decreased Fatigue Tolerance In Diaphragm Muscle Of Slow Troponin T Knockdown Mice
    Biophysical Journal, 2009
    Co-Authors: Hanzhong Feng, Bin Wei, Jian Ping Jin
    Abstract:

    The loss of slow skeletal Muscle troponin T (TnT) results in a severe type of nemaline myopathy in the Amish (ANM). The genes encoding TnT and troponin I (TnI) are closely linked in pairs in which the 5′-enhancer region of the slow TnT gene overlaps with the cardiac TnI gene. In a mouse line with the entire cardiac TnI gene deleted, a partial destruction of the slow TnT gene promoter produces a knockdown effect. By crossing with transgenic mouse lines that over-express a core structure of cardiac TnI (cTnI-ND) under the control of cloned alpha-MHC promoter, we rescued the postnatal lethality of the cardiac TnI gene-deleted mice with no detrimental cardiac phenotypes or leaking expression in non-cardiac tissues. The double transgenic mice exhibited decreased expression of slow TnT mRNA and protein in adult Diaphragm Muscle. Functional analysis of isolated Muscle strips showed that the slow TnT deficient (sTnT-KD) Diaphragm had significantly decreased fatigue tolerance evident by the faster decrease in force and slower rate of recovery as compared with that in wild type controls. As a consequence of slow TnT deficiency, the sTnT-KD Diaphragm Muscle contained a higher proportion of fast TnT, decreased slow TnI with increased fast TnI, and decreased type I myosin with increased type II myosin. Consistent with the switch toward fast myofilament contents, the sTnT-KD Diaphragm Muscle produced higher specific tension in twitch and tetanic contractions as well as shorter time to develop peak tension in twitch contractions. The decreased fatigue tolerance of sTnT-KD Diaphragm Muscle explains the terminal respiratory failure seen in virtually all ANM patients and this double transgenic mouse model provides a useful experimental system to study the pathogenesis and treatment of ANM.