Striking denervation of neuromuscular junctions without lumbar motoneuron loss in geriatric mouse muscle.

Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation.

A single 30 min treadmill exercise session is suitable for 'proof-of concept studies' in adult mdx mice: a comparison of the early consequences of two different treadmill protocols.

The extent of muscle pathology in sedentary adult mdx mice is very low and treadmill exercise is often used to increase myofibre necrosis; however, the early events in dystrophic muscle and blood in response to treadmill exercise (leading to myofibre necrosis) are unknown. This study describes in detail two standardised protocols for the treadmill exercise of mdx mice and profiles changes in molecular and cellular events after a single 30 min treadmill session (Protocol A) or after 4 weeks of (twice weekly) treadmill exercise (Protocol B). Both treadmill protocols increased multiple markers of muscle damage.

Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography.

Three-dimensional optical coherence tomography (3D-OCT) was used to image the structure and pathology of skeletal muscle tissue from the treadmill-exercised mdx mouse model of human Duchenne muscular dystrophy. Optical coherence tomography (OCT) images of excised muscle samples were compared with co-registered hematoxylin and eosin-stained and Evans blue dye fluorescence histology. We show, for the first time, structural 3D-OCT images of skeletal muscle dystropathology well correlated with co-located histology.

Quantification of ceroid and lipofuscin in skeletal muscle.

Ceroid and lipofuscin are autofluorescent granules thought to be generated as a consequence of chronic oxidative stress. Because ceroid and lipofuscin are persistent in tissue, their measurement can provide a lifetime history of exposure to chronic oxidative stress. Although ceroid and lipofuscin can be measured by quantification of autofluorescent granules, current methods rely on subjective assessment.

Growing muscle has different sarcolemmal properties from adult muscle: a proposal with scientific and clinical implications: reasons to reassess skeletal muscle molecular dynamics, cellular responses and suitability of experimental models of muscle disorders.

We hypothesise that the sarcolemma of an actively growing myofibre has different properties to the sarcolemma of a mature adult myofibre. Such fundamentally different properties have clinical consequences for the onset, and potential therapeutic targets, of various skeletal muscle diseases that first manifest either during childhood (e.g.

A growth stimulus is needed for IGF-1 to induce skeletal muscle hypertrophy in vivo.

Here, we characterise new strains of normal and dystrophic (mdx) mice that overexpress Class 2 IGF-1 Ea in skeletal myofibres. We show that transgenic mice have increased muscle levels of IGF-1 (approximately 13-26 fold) and show striking muscle hypertrophy (approximately 24-56% increase in mass). Adult normal muscles were resistant to elevated IGF-1; they reached adult steady state and maintained the same mass from 3 to 12 months.

Delayed but excellent myogenic stem cell response of regenerating geriatric skeletal muscles in mice.

The ability of very old animals to make new muscle after injury remains controversial. This issue has major implications for the regenerative potential of damaged geriatric human muscle, to age-related loss of muscle mass (sarcopenia) and to the proposed need for muscle stem cell therapy for the aged. To further address issues of inherent myogenic capacity and the role of host systemic factors in new muscle formation, whole muscle grafts were transplanted between geriatric (aged 27-29 months) and young (3 months) C57Bl/6J mice and compared with autografts in geriatric and young mice.

Use of pifithrin to inhibit p53-mediated signalling of TNF in dystrophic muscles of mdx mice.

Tumour Necrosis Factor (TNF) plays a major role in exacerbating necrosis of dystrophic muscle; however, the precise molecular mechanism underlying this effect of TNF is unknown. This study investigates the role that p53 plays in TNF-mediated necrosis of dystrophic myofibres by inhibiting p53 using pifithrin-alpha and three pifithrin-beta analogues. Tissue culture studies using C2C12 myoblasts established that pifithrin-alpha was toxic to differentiating myoblasts at concentrations greater than 10 muM.

Oxidative stress as a therapeutic target during muscle wasting: considering the complex interactions.

Purpose Of Review: The aim of this overview is to highlight the multiple ways in which oxidative stress could be exacerbating muscle wasting. Understanding these interactions in vivo will assist in identifying opportunities for more targeted therapies to reduce skeletal muscle wasting.

Recent Findings: There are many excellent reviews describing how oxidative stress can damage cellular macromolecules, as well as cause deleterious effects through the modulation of signalling pathways.

Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle.

1. Inflammation, particularly the pro-inflammatory cytokine tumour necrosis factor (TNF), increases necrosis of skeletal muscle. Depletion of inflammatory cells, such as neutrophils, cromolyn blockade of mast cell degranulation or pharmacological blockade of TNF reduces necrosis of dystrophic myofibres in the mdx mouse model of the lethal childhood disease Duchenne muscular dystrophy (DMD).

Muscle-specific overexpression of IGF-I improves E-C coupling in skeletal muscle fibers from dystrophic mdx mice.

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by the absence of functional dystrophin. Abnormal excitation-contraction (E-C) coupling has been reported in dystrophic muscle fibers from mdx mice, and alterations in E-C coupling components may occur as a direct result of dystrophin deficiency. We hypothesized that muscle-specific overexpression of insulin-growth factor-1 (IGF-I) would reduce E-C coupling failure in mdx muscle.

Of bears, frogs, meat, mice and men: complexity of factors affecting skeletal muscle mass and fat.

Extreme loss of skeletal muscle mass (atrophy) occurs in human muscles that are not used. In striking contrast, skeletal muscles do not rapidly waste away in hibernating mammals such as bears, or aestivating frogs, subjected to many months of inactivity and starvation. What factors regulate skeletal muscle mass and what mechanisms protect against muscle atrophy in some species? Severe atrophy also occurs with ageing and there is much clinical interest in reducing such loss of muscle mass and strength (sarcopenia).

Silencing TNFalpha activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice.

Dramatic clinical success in the treatment of chronic inflammatory diseases has resulted from the use of anti-cytokine therapies including specific blocking antibodies, soluble receptors and traps to silence the actions of inflammatory cytokines such as tumour necrosis factor alpha (TNFalpha) and interleukin-1 (IL-1). Two agents used clinically to block the functional activity of TNFalpha protein are Remicade (an antibody) and Enbrel (a soluble TNF receptor). These tools are now being extended to many other clinical disorders.

Reconciling data from transgenic mice that overexpress IGF-I specifically in skeletal muscle.

Transgenic mice that overexpress insulin-like growth factor-1 (IGF-I) specifically in skeletal muscle have generated much information about the role of this factor for muscle growth and remodelling and provide insight for therapeutic applications of IGF-I for different pathological states and ageing. However, difficulties arise when attempting to critically compare the significance of data obtained in vivo by using different genetically engineered mouse lines and various experimental models. Complications arise due to complexity of the IGF-I system, since multiple transcripts of the IGF-I gene encode different isoforms generated by alternate promoter usage, differential splicing and post-translational modification, and how IGF-I gene expression relates to its diverse autocrine, paracrine and endocrine modes of action in vivo has still to be elucidated.

Insulin-like growth factor I slows the rate of denervation induced skeletal muscle atrophy.

Loss of the nerve supply to skeletal muscle results in a relentless loss of muscle mass (atrophy) over time. The ability of insulin-like growth factor-1 to reduce atrophy resulting from denervation was examined after transection of the sciatic nerve in transgenic MLC/mIGF-1 mice that over-express mIGF-1 specifically in differentiated myofibres. The cross sectional area (CSA) of all types of myofibres and specifically type IIB myofibres was measured in tibialis anterior muscles from transgenic and wild-type mice at 28 days after denervation.

Targeted expression of insulin-like growth factor-I reduces early myofiber necrosis in dystrophic mdx mice.

Necrosis of dystrophic myofibers in Duchenne muscular dystrophy and mdx mice results from defects in the subsarcolemmal protein dystrophin that cause membrane fragility and tears in the sarcolemma, and these lead to the destruction of the myofibers. The present study specifically tests whether overexpression of mIGF-1 in mdx/mIGF-1 transgenic mice reduces myofiber breakdown during the acute onset phase of dystrophy (at 21 days). The extent of muscle damage and Evans blue dye (EBD) staining of myofibers was quantitated histologically for mdx/mIGF-1 and their mdx littermates from 15 to 30 days of age.

Early regeneration of whole skeletal muscle grafts is unaffected by overexpression of IGF-1 in MLC/mIGF-1 transgenic mice.

Early myogenic events in regenerating whole muscle grafts were compared between transgenic MLC/mIGF-1 mice with skeletal muscle-specific overexpression of the Exon-1 Ea isoform of insulin-like growth factor-1 (mIGF-1) and control FVB mice, from day 3 to day 21 after transplantation. Immunocytochemistry with antibodies against desmin showed that skeletal muscle-specific overexpression of IGF-1 did not affect the pattern of myoblast activation or proliferation or the onset and number of myotubes formed in regenerating whole muscle grafts. Hypertrophied myotubes were observed in MLC/mIGF grafts at day 7 after transplantation, although such hypertrophy was transient, and the transgenic and control grafts had a similar appearance at later time points (days 10, 14, and 21).