Skeletal muscle mass increases during postnatal development through a process of hypertrophy, i.e. enlargement of individual muscle fibers, and a similar process may be induced in adult skeletal muscle in response to contractile activity, such as strength exercise, and specific hormones, such as androgens and β-adrenergic agonists. Muscle hypertrophy occurs when the overall rates of protein synthesis exceed the rates of protein degradation. Two major signaling pathways control protein synthesis, the IGF1-Akt-mTOR pathway, acting as a positive regulator, and the myostatin-Smad2/3 pathway, acting as a negative regulator, and additional pathways have recently been identified. Proliferation and fusion of satellite cells, leading to an increase in the number of myonuclei, may also contribute to muscle growth during early but not late stages of postnatal development and in some forms of muscle hypertrophy in the adult. Muscle atrophy occurs when protein degradation rates exceed protein synthesis, and may be induced in adult skeletal muscle in a variety of conditions, including starvation, denervation, cancer cachexia, heart failure and aging. Two major protein degradation pathways, the proteasomal and the autophagic-lysosomal pathways, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These pathways involve a variety of atrophy-related genes or atrogenes, which are controlled by specific transcription factors, such as FoxO3, which is negatively regulated by Akt, and NF-κB, which is activated by inflammatory cytokines.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.12253

Mechanisms regulating skeletal muscle growth and atrophy

Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting.

Muscle wasting in disease: molecular mechanisms and promising therapies

Among all neurotrophins, brain-derived neurotrophic factor (BDNF) stands out for its high level of expression in the brain and its potent effects on synapses. It is now widely accepted that the main function of BDNF in the adult brain is to regulate synapses, with structural and functional effects ranging from short-term to long-lasting, on excitatory or inhibitory synapses, in many brain regions. The diverse effects of BDNF on brain synapses stem from its complex downstream signaling cascades, as well as the diametrically opposing effects of the pro- and mature form through distinct receptors, TrkB and p75NTR. Many aspects of BDNF cell biology are regulated by neuronal activity. The synergistic interactions between neuronal activity and synaptic plasticity by BDNF make it an ideal and essential regulator of cellular processes that underlie cognition and other complex behaviors. Indeed, numerous studies firmly established that BDNF plays a critical role in hippocampal long-term potentiation (LTP), a long-term enhancement of synaptic efficacy thought to underlie learning and memory. Converging evidence now strongly suggest that deficits in BDNF signaling contribute to the pathogenesis of several major diseases and disorders such as Huntington’s disease, Alzheimer’s disease, and depression. Thus, manipulating BDNF pathways represents a viable treatment approach to a variety of neurological and psychiatric disorders.

BDNF and Synaptic Plasticity, Cognitive Function, and Dysfunction

The molecular mechanisms underlying skeletal muscle maintenance involve interplay between multiple signaling pathways. Under normal physiological conditions, a network of interconnected signals serves to control and coordinate hypertrophic and atrophic messages, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed "atrophy", is a diagnostic feature of cachexia seen in settings of cancer, heart disease, chronic obstructive pulmonary disease, kidney disease, and burns. Cachexia increases the likelihood of death from these already serious diseases. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce differentiation and post-injury regeneration, which are also essential for the maintenance of skeletal muscle mass. In this review, we summarize and discuss the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle.

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Signaling pathways controlling skeletal muscle mass.

Estradiol and cognitive function: past, present and future.

Sarcopenia is the progressive loss of skeletal muscle mass and function with advancing age, leading to reduced mobility and quality of life. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the decline in mass and function of muscles of aged mice and that apoptosis would be reduced. Eighteen-month-old C57BL/6 mice were treated for 14 wk with a once-weekly injection of saline (control, n=9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg; n=12). PF-354 prevented the age-related reduction in body mass and increased soleus, gastrocnemius, and quadriceps muscle mass (P<0.05). PF-354 increased fiber cross-sectional area by 12% and enhanced maximum in situ force of tibialis anterior (TA) muscles by 35% (P<0.05). PF-354 increased the proportion of type IIa fibers by 114% (P<0.01) and enhanced activity of oxidative enzymes (SDH) by 39% (P<0.01). PF-354 reduced markers of apoptosis in TA muscle cross-sections by 56% (P<0.03) and reduced caspase3 mRNA by 65% (P<0.04). Antibody-directed myostatin inhibition attenuated the decline in mass and function of muscles of aging mice, in part, by reducing apoptosis. These observations identify novel roles for myostatin in regulation of muscle mass and highlight the therapeutic potential of antibody-directed myostatin inhibition for sarcopenia.

Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function

Cancer cachexia describes the progressive skeletal muscle wasting and weakness that is associated with many cancers. It impairs quality of life and accounts for >20% of all cancer-related deaths. The main outcome that affects quality of life and mortality is loss of skeletal muscle function and so preclinical models should exhibit similar functional impairments in order to maximize translational outcomes. Mice bearing colon-26 (C-26) tumors are commonly used in cancer cachexia studies but few studies have provided comprehensive assessments of physiological and metabolic impairment, especially those factors that impact quality of life. Our aim was to characterize functional impairments in mildly and severely affected cachectic mice, and determine the suitability of these mice as a preclinical model. Metabolic abnormalities are also evident in cachectic patients and we investigated whether C-26-tumor-bearing mice had similar metabolic aberrations. Twelve-week-old CD2F1 mice received a subcutaneous injection of PBS (control) or C-26 tumor cells. After 18-20 days, assessments were made of grip strength, rotarod performance, locomotor activity, whole body metabolism, and contractile properties of tibialis anterior (TA) muscles (in situ) and diaphragm muscle strips (in vitro). Injection of C-26 cells reduced body and muscle mass, and epididymal fat mass. C-26-tumor-bearing mice exhibited lower grip strength and rotarod performance. Locomotor activity was impaired following C-26 injection, with reductions in movement distance, duration and speed compared with controls. TA muscles from C-26-tumor-bearing mice had lower maximum force (-27%) and were more susceptible to fatigue. Maximum specific (normalized) force of diaphragm muscle strips was reduced (-10%) with C-26 injection, and force during fatiguing stimulation was also lower. C-26-tumor-bearing mice had reduced carbohydrate oxidation and increased fat oxidation compared with controls. The range and consistency of functional and metabolic impairments in C-26-tumor-bearing mice confirm their suitability as a preclinical model for cancer cachexia. We recommend the use of these comprehensive functional assessments to maximize the translation of findings to more accurately identify effective treatments for cancer cachexia.

/pdf/importance-of-functional-and-metabolic-impairments-in-the-2am1r5rxaf.pdf

Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia.

Chronic stimulation of β-adrenoceptors with β-adrenoceptor agonists (β-agonists) can induce substantial skeletal muscle hypertrophy, but the mechanisms mediating this muscle growth have yet to be elucidated. We investigated whether chronic β-adrenoceptor stimulation in mice with the β-agonist formoterol alters the muscle anabolic response following β-adrenoceptor stimulation. Twelve-week-old C57BL/6 mice were treated for up to 28 days with a once-daily injection of either saline (control, n= 9) or formoterol (100 μg kg−1; n= 9). Rates of muscle protein synthesis were assessed at either 1, 7 or 28 days of treatment, 6 h after injection. Protein synthesis rates were higher in formoterol-treated mice at day 7 (∼1.5-fold, P < 0.05), but not at day 1 or 28. The increased muscle protein synthesis was associated with increased phosphorylation of S6K1 (r= 0.49, P < 0.01). Formoterol treatment acutely reduced maximal calpain activity by ∼25% (P < 0.05) but did not affect atrogin-1 protein levels and proteasome-mediated proteolytic activity, despite significantly enhanced phosphorylation of Akt (P < 0.05). Formoterol increased CREB phosphorylation by ∼30% (P < 0.05) and PPARγ coactivator-1α (PGC-1α) by 11-fold (P < 0.05) on day 1 only. These observations identify that formoterol treatment induces muscle anabolism, by reducing calpain activity and by enhancing protein synthesis via increased PI-3 kinase/Akt signalling.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2010.196725

Cellular mechanisms underlying temporal changes in skeletal muscle protein synthesis and breakdown during chronic β-adrenoceptor stimulation in mice

Previous reports have described increases in the size and number of cholinergic neurons in the basal forebrain in p75 neurotrophin receptor (p75(NTR)) knockout mice. In an earlier study, we also found improved spatial memory in these mice, raising the possibility that p75(NTR) regulates hippocampal function by its effects on the cholinergic basal forebrain. We therefore investigated hippocampal long-term potentiation in p75(NTR) knockout mice that shared the same genetic background as control 129/Sv mice. We also investigated heterozygous mice, carrying just one functional p75(NTR) allele. The p75(NTR) knockout mice had enhanced long-term potentiation in the Schafer collateral fiber synapses of the hippocampus. Heterozygous mice had an intermediate level, greater than controls but less than knockout mice. Hippocampal choline acetyltransferase activity was also markedly elevated in p75(NTR) knockout mice, with a smaller increase in heterozygous mice. In the Barnes maze, p75(NTR) knockout mice displayed markedly superior learning to controls, and this was evident over the three age brackets tested. At each age, the performance of heterozygous mice was intermediate to the other groups. In the open field test, p75(NTR) knockout mice exhibited greater stress-related behavioral responses, including freezing, than did control animals. There were no differences between the three groups in a test of olfactory function. The dose-dependent effects of p75(NTR) gene copy number on hippocampal plasticity and spatial memory indicate that p75(NTR) has profound effects on hippocampal function. Bearing in mind that p75(NTR) is very sparsely expressed in the adult hippocampus and has a potent effect on hippocampal choline acetyltransferase activity, the effects of p75(NTR) on hippocampal function are likely to be mediated indirectly, by its actions on basal forebrain cholinergic neurons.

Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice.

Estrogen receptors are expressed in several areas of the brain associated with cognition, including the basal forebrain cholinergic nuclei, and numerous reports have described improvements in memory in response to estrogen supplementation. The relationship between estrogen's effects on the basal cholinergic system and improvements in cognitive function, however, are obscure. We therefore undertook a study to determine the effects of estrogen on several parameters of the cholinergic system in ovariectomized rats and measured the concomitant effects on performance in the Barnes maze, a test of spatial memory. Six weeks of estradiol treatment caused an increase in choline acetyltransferase activity throughout the projection fields of the basal forebrain, including the hippocampal formation (14%), olfactory bulb (30%), and cerebral cortex (35%). Estrogen treatment also caused an increase in cell soma size of cholinergic neurons in the horizontal diagonal limb of the band of Broca and in the basal nucleus of Meynert. There was no change in the number of neurons positive for p75NTR, nor in the level of p75NTR expression per neuron. Barnes maze performance was markedly improved after estradiol treatment, reinforcing the view that estrogen has beneficial cognitive effects, particularly on spatial memory. The beneficial cognitive effect was likely mediated in part by stimulation of the basal forebrain cholinergic system, especially in its neocortical projection, but was not associated with changes in the level of p75NTR expression. © 2008 Wiley-Liss, Inc.

Jennifer Trieu

Papers

Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and function

Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia.

Cellular mechanisms underlying temporal changes in skeletal muscle protein synthesis and breakdown during chronic β-adrenoceptor stimulation in mice

Enhanced spatial memory and hippocampal long-term potentiation in p75 neurotrophin receptor knockout mice.

Effects of estrogen on basal forebrain cholinergic neurons and spatial learning.