title: The role of myostatin during postnatal myogenesis and sarcopenia

authors: Siriett, Victoria Katherine

subjects: myostatin

abstract: Myostatin, a TGF-β superfamily member, is a key negative regulator of embryonic and postnatal muscle growth. In order to further elucidate the role of myostatin during postnatal growth, several lines of investigation were undertaken in mice. Analysis of myostatin downstream target genes identified several known and unknown genes. From these, the regulation of an androgen receptor binding co-factor, ARA70, was selected for further investigation. Reverse Northern analysis on the differentially expressed cDNA library indicated an increased expression of ARA70 in myostatin-null muscles, which was later confirmed by Northern blot and semi-quantitative PCR analysis. In corroboration, treatment of myoblast cultures with exogenous myostatin resulted in the down-regulation of ARA70, confirming that myostatin is a negative regulator of ARA70 gene expression. The role of myostatin during sarcopenia, a progressive age-related loss of skeletal muscle mass and strength, was also investigated. The atrophy associated with sarcopenia is frequently correlated with insufficient muscle regeneration, resulting from an impaired propensity of satellite cells to activate and a subsequent decline in myogenesis. Myostatin is a known inhibitor of postnatal satellite cell activation and muscle regeneration, thus muscle mass and regeneration, and satellite cell behaviour were examined in young and aged myostatin-null mice. Myostatin-null mice had increased individual muscle weights, as a consequence of massive fibre hypertrophy and hyperplasia, and an increased proportion of type IIB fibres. Aging induced oxidative fibre type changes and atrophy in the wild-type muscle while no fibre type switching was observed in the myostatin-null muscle and atrophy was minimal. No decrease in satellite cell numbers was observed with aging in both genotypes; though a gradual decline in the number of activated satellite cells was noted during aging. However, both young and aged myostatin-null mice displayed increased satellite cells and activation compared to wild-type mice, suggesting a greater myogenic potential in the myostatin-null satellite cells. Consistent with this, aged myostatin-null myoblasts proliferated faster and displayed a higher fusion index during differentiation than the aged wild-type myoblasts, confirming that the reduced sarcopenia in the myostatin-null mice was due to a preserved increase in the myoblast myogenic activity. An increase in a Pax7-only myoblast population from myostatin-null muscle indicated an enhanced satellite cell self-renewal process, consistent with the increased satellite cell number observed on the myostatin-null muscle fibres. Additionally, muscle regeneration of aged myostatin-null muscle following notexin injury was accelerated, and fibre hypertrophy and type were recovered with regeneration, unlike the aged wild-type muscle. Testing the therapeutic value of a myostatin antagonist, Mstn-ant1, indicated that a short term blockade of myostatin by the antagonist significantly enhanced muscle regeneration in aged mice after injury and during sarcopenia. Antagonism of myostatin led to satellite cell activation, increased Pax7 and MyoD protein levels, and greater myoblast and macrophage cell migration culminating in enhanced muscle regeneration in the aged mice. 
In conclusion, the hypertrophic phenotype associated with myostatin-null mice may in part result from increased androgen receptor (AR) activity due to the up-regulation of ARA70, given that increased expression of the AR leads to hypertrophy. Additionally, the increased muscle mass in myostatin-null mice is likely to result from an augmented myogenic potential and self-renewal process. Overall, a prolonged absence of myostatin reduced sarcopenia and the associated loss of muscle regenerative capacity. Furthermore, the antagonism of myostatin displayed significant therapeutic potential in the alleviation of sarcopenia, through the restoration of the myogenic and inflammatory responses in the aged environment. Thus, the research work clearly demonstrates the role of myostatin in sarcopenia, and documents for the first time a valid therapeutic for alleviating sarcopenia.

text: The role of myostatin during postnatal myogenesis and sarcopenia Myostatin, a TGF-β superfamily member, is a key negative regulator of embryonic and postnatal muscle growth. In order to further elucidate the role of myostatin during postnatal growth, several lines of investigation were undertaken in mice. Analysis of myostatin downstream target genes identified several known and unknown genes. From these, the regulation of an androgen receptor binding co-factor, ARA70, was selected for further investigation. Reverse Northern analysis on the differentially expressed cDNA library indicated an increased expression of ARA70 in myostatin-null muscles, which was later confirmed by Northern blot and semi-quantitative PCR analysis. In corroboration, treatment of myoblast cultures with exogenous myostatin resulted in the down-regulation of ARA70, confirming that myostatin is a negative regulator of ARA70 gene expression. The role of myostatin during sarcopenia, a progressive age-related loss of skeletal muscle mass and strength, was also investigated. The atrophy associated with sarcopenia is frequently correlated with insufficient muscle regeneration, resulting from an impaired propensity of satellite cells to activate and a subsequent decline in myogenesis. Myostatin is a known inhibitor of postnatal satellite cell activation and muscle regeneration, thus muscle mass and regeneration, and satellite cell behaviour were examined in young and aged myostatin-null mice. Myostatin-null mice had increased individual muscle weights, as a consequence of massive fibre hypertrophy and hyperplasia, and an increased proportion of type IIB fibres. Aging induced oxidative fibre type changes and atrophy in the wild-type muscle while no fibre type switching was observed in the myostatin-null muscle and atrophy was minimal. No decrease in satellite cell numbers was observed with aging in both genotypes; though a gradual decline in the number of activated satellite cells was noted during aging. However, both young and aged myostatin-null mice displayed increased satellite cells and activation compared to wild-type mice, suggesting a greater myogenic potential in the myostatin-null satellite cells. Consistent with this, aged myostatin-null myoblasts proliferated faster and displayed a higher fusion index during differentiation than the aged wild-type myoblasts, confirming that the reduced sarcopenia in the myostatin-null mice was due to a preserved increase in the myoblast myogenic activity. An increase in a Pax7-only myoblast population from myostatin-null muscle indicated an enhanced satellite cell self-renewal process, consistent with the increased satellite cell number observed on the myostatin-null muscle fibres. Additionally, muscle regeneration of aged myostatin-null muscle following notexin injury was accelerated, and fibre hypertrophy and type were recovered with regeneration, unlike the aged wild-type muscle. Testing the therapeutic value of a myostatin antagonist, Mstn-ant1, indicated that a short term blockade of myostatin by the antagonist significantly enhanced muscle regeneration in aged mice after injury and during sarcopenia. Antagonism of myostatin led to satellite cell activation, increased Pax7 and MyoD protein levels, and greater myoblast and macrophage cell migration culminating in enhanced muscle regeneration in the aged mice. 
In conclusion, the hypertrophic phenotype associated with myostatin-null mice may in part result from increased androgen receptor (AR) activity due to the up-regulation of ARA70, given that increased expression of the AR leads to hypertrophy. Additionally, the increased muscle mass in myostatin-null mice is likely to result from an augmented myogenic potential and self-renewal process. Overall, a prolonged absence of myostatin reduced sarcopenia and the associated loss of muscle regenerative capacity. Furthermore, the antagonism of myostatin displayed significant therapeutic potential in the alleviation of sarcopenia, through the restoration of the myogenic and inflammatory responses in the aged environment. Thus, the research work clearly demonstrates the role of myostatin in sarcopenia, and documents for the first time a valid therapeutic for alleviating sarcopenia.

year: 2007

title: Morphodynamics of the Whitianga Tidal Inlet and Buffalo Bay, New Zealand

authors: Steeghs, Lauren

subjects: Eddy formation

abstract: The primary aim of this study was to investigate the sedimentation processes within Buffalo Bay, particularly within and adjacent to the Whitianga tidal inlet, in order to ascertain reasons for the shoaling at both the inlet, and the identified shallow zone around Pandora Rock. 

Comparison of historic bathymetries suggests the ebb delta and ebb discharge channel of the Whitianga tidal inlet are rapidly accreting and the ebb tidal discharge channel is gradually migrating northeast towards Whakapenui Point.  Accretion rates of up to 25 cm y-1 were calculated in the ebb delta and inlet discharge channel area between 1979 and 1995 and aerial photo comparisons suggest the ebb delta area had increased by 400 % between 1990 and 2002.  Results of the hydrodynamic and sediment transport modelling suggest the rapid accretion in the ebb delta vicinity is likely to be caused by a combination of catchment estuary inputs, which are deposited on the ebb tide as the ebb flow decelerates over the ebb delta, and inputs that have been moved south along Buffalo Beach by flood currents and an eddy that forms landward of the ebb tidal discharge.  Residual tidal velocities further suggest a deposition zone in the ebb delta vicinity resulting from opposing currents and the deceleration of currents.  

Hydrodynamic modelling results indicate the isolated shallow zone around Pandora rock appears to be caused by a transient eddy in the southern section of Buffalo Bay.  The eddy is formed by the ebb tidal discharge from the inlet.  Accretion probably occurs in the centre of the eddy which moves north as the ebb tide progresses.  

Results obtained from a current meter and sediment trap deployed in northern Buffalo Bay suggest suspended sediment transport is minimal in northern Buffalo Bay, only occurring with large wave activity.   Results of the hydrodynamic and sediment transport modelling further demonstrate that this area experiences low flow velocities, and has little interaction with the rest of Buffalo Bay.  The minimal sediment input to this area, combined with the occasional erosion of the seafloor, primarily by wave activity, is thought to have resulted in long term erosion of northwestern Buffalo Bay between 1938 and 1979.  Although the beach and nearshore is eroding, it is likely the addition of sediment would act to stabilise this section of eroding beach.  Renourishment material could be provided by the ebb delta, the southern tip of Buffalo Bay or the isolated sandbar northeast of the inlet entrance.

text: Morphodynamics of the Whitianga Tidal Inlet and Buffalo Bay, New Zealand The primary aim of this study was to investigate the sedimentation processes within Buffalo Bay, particularly within and adjacent to the Whitianga tidal inlet, in order to ascertain reasons for the shoaling at both the inlet, and the identified shallow zone around Pandora Rock. 

Comparison of historic bathymetries suggests the ebb delta and ebb discharge channel of the Whitianga tidal inlet are rapidly accreting and the ebb tidal discharge channel is gradually migrating northeast towards Whakapenui Point.  Accretion rates of up to 25 cm y-1 were calculated in the ebb delta and inlet discharge channel area between 1979 and 1995 and aerial photo comparisons suggest the ebb delta area had increased by 400 % between 1990 and 2002.  Results of the hydrodynamic and sediment transport modelling suggest the rapid accretion in the ebb delta vicinity is likely to be caused by a combination of catchment estuary inputs, which are deposited on the ebb tide as the ebb flow decelerates over the ebb delta, and inputs that have been moved south along Buffalo Beach by flood currents and an eddy that forms landward of the ebb tidal discharge.  Residual tidal velocities further suggest a deposition zone in the ebb delta vicinity resulting from opposing currents and the deceleration of currents.  

Hydrodynamic modelling results indicate the isolated shallow zone around Pandora rock appears to be caused by a transient eddy in the southern section of Buffalo Bay.  The eddy is formed by the ebb tidal discharge from the inlet.  Accretion probably occurs in the centre of the eddy which moves north as the ebb tide progresses.  

Results obtained from a current meter and sediment trap deployed in northern Buffalo Bay suggest suspended sediment transport is minimal in northern Buffalo Bay, only occurring with large wave activity.   Results of the hydrodynamic and sediment transport modelling further demonstrate that this area experiences low flow velocities, and has little interaction with the rest of Buffalo Bay.  The minimal sediment input to this area, combined with the occasional erosion of the seafloor, primarily by wave activity, is thought to have resulted in long term erosion of northwestern Buffalo Bay between 1938 and 1979.  Although the beach and nearshore is eroding, it is likely the addition of sediment would act to stabilise this section of eroding beach.  Renourishment material could be provided by the ebb delta, the southern tip of Buffalo Bay or the isolated sandbar northeast of the inlet entrance.

year: 2007

title: A survey of psychologists’ opinions and behaviours on aspects of Maori mental health

authors: Sawrey, Richard

subjects: Maori

abstract: In the majority of settings where psychologists work, particularly in State health and justice settings, Maori people are substantially over represented relative to their numbers in the general population (Durie, 1987). This situation has raised serious questions about the adequacy of both mental health services and professionals in their provision of appropriate services for Maori people. (Hui Whakaoranga, 1984; Durie, 1985). Recommendations have been given to address these deficiencies. Te Hui Whakaoranga (l984) recommended a recruitment programme for Maori into health professions and training for health workers in Maori culture. The Committee of Inquiry into Procedures used in Psychiatric Hospitals (1988) pointed out that health professionals are rarely educated in taha Maori or the application of taha Maori to the service they provide. They stated that many current training programmes create a barrier to Maori people entering the health professions. They recommended that changes occur in both the in - service and basic training of health professionals.

text: A survey of psychologists’ opinions and behaviours on aspects of Maori mental health In the majority of settings where psychologists work, particularly in State health and justice settings, Maori people are substantially over represented relative to their numbers in the general population (Durie, 1987). This situation has raised serious questions about the adequacy of both mental health services and professionals in their provision of appropriate services for Maori people. (Hui Whakaoranga, 1984; Durie, 1985). Recommendations have been given to address these deficiencies. Te Hui Whakaoranga (l984) recommended a recruitment programme for Maori into health professions and training for health workers in Maori culture. The Committee of Inquiry into Procedures used in Psychiatric Hospitals (1988) pointed out that health professionals are rarely educated in taha Maori or the application of taha Maori to the service they provide. They stated that many current training programmes create a barrier to Maori people entering the health professions. They recommended that changes occur in both the in - service and basic training of health professionals.

year: 1993