Myostatin is a secreted protein that normally functions as a negative regulator of muscle growth. Agents capable of blocking the myostatin signaling pathway could have important applications for treating human muscle degenerative diseases as well as for enhancing livestock production. Here we describe a potent myostatin inhibitor, a soluble form of the activin type IIB receptor (ACVR2B), which can cause dramatic increases in muscle mass (up to 60% in 2 weeks) when injected into wild-type mice. Furthermore, we show that the effect of the soluble receptor is attenuated but not eliminated in Mstn ؊/؊ mice, suggesting that at least one other ligand in addition to myostatin normally functions to limit muscle growth. Finally, we provide genetic evidence that these ligands signal through both activin type II receptors, ACVR2 and ACVR2B, to regulate muscle growth in vivo. Mice carrying a targeted mutation in the myostatin gene have muscles that are about twice the normal size as a result of a combination of muscle fiber hyperplasia and hypertrophy (2). Myostatin appears to play a similar role in other species as well; naturally occurring mutations in the myostatin gene have been shown to be responsible for the double-muscling phenotype in cattle (3-6), and recent studies have demonstrated that a human baby with approximately twice the normal muscle mass is also homozygous for a loss-of-function mutation in the MSTN gene (7). These findings have raised the possibility that agents capable of targeting the myostatin signaling pathway may be useful for increasing muscle mass for both agricultural and human therapeutic applications. In this regard, loss of myostatin signaling has been shown to have beneficial effects in mouse models of muscle degenerative (8, 9) and metabolic (10) diseases.Various myostatin-binding proteins have been identified that are capable of inhibiting myostatin activity in vitro (8,(11)(12)(13)(14)(15)(16). Two of these proteins, the JA16 neutralizing monoclonal antibody (Ab) directed against myostatin (8, 15) and a mutant form of the myostatin propeptide resistant to members of the BMP-1͞tolloid family of metalloproteases (16), have been shown to be capable of increasing muscle mass by Ϸ25% when administered to wild-type (WT) mice. To determine whether these increases in muscle growth are the maximal achievable by targeting this signaling pathway, we sought additional myostatin inhibitors that might have a broader specificity in their ability to target additional members of the TGF-␤ superfamily. Previous studies have demonstrated that myostatin is capable of binding the two activin type II receptors, ACVR2B and, to a lesser extent, ACVR2, in transfected COS cells (11,17). Moreover, transgenic mice in which a myosin light chain promoter͞ enhancer was used to express a truncated form of ACVR2B in skeletal muscle were found to have dramatic increases in muscle mass (11). Because the activin type II receptors have been shown to be capable of binding a number of other TGF-␤ family members in addition to ...

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons (MNs) that causes paralysis. Some forms of ALS are inherited, caused by mutations in the superoxide dismutase-1 (SOD1) gene. The mechanisms of human mutant SOD1 (mSOD1) toxicity to MNs are unresolved. Mitochondria in MNs might be key sites for ALS pathogenesis, but cause-effect relationships between mSOD1 and mitochrondiopathy need further study. We used transgenic mSOD1 mice to test the hypothesis that the mitochondrial permeability transition pore (mPTP) is involved in the MN degeneration of ALS. Components of the multi-protein mPTP are expressed highly in mouse MNs, including the voltage-dependent anion channel, adenine nucleotide translocator (ANT), and cyclophilin D (CyPD), and are present in mitochondria marked by manganese SOD. MNs in pre-symptomatic mSOD1-G93A mice form swollen megamitochondria with CyPD immunoreactivity. Early disease is associated with mitochondrial cristae remodeling and matrix vesiculation in ventral horn neuron dendrites. MN cell bodies accumulate mitochondria derived from the distal axons projecting to skeletal muscle. Incipient disease in spinal cord is associated with increased oxidative and nitrative stress, indicated by protein carbonyls and nitration of CyPD and ANT. Reducing the levels of CyPD by genetic ablation significantly delays disease onset and extends the lifespan of G93A-mSOD1 mice expressing high and low levels of mutant protein in a gender-dependent pattern. These results demonstrate that mitochondria have causal roles in the disease mechanisms in MNs in ALS mice. This work defines a new mitochondrial mechanism for MN degeneration in ALS.

The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.

Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate) has demonstrated effectiveness orally in the treatment and prevention of postmenopausal osteoporosis, corticosteroid-induced osteoporosis and Paget's disease of the bone. Its primary mechanism of action involves the inhibition of osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of alendronate must be interpreted in the context of its unique properties, which include targeting to the skeleton and incorporation into the skeletal matrix. Preclinically, alendronate is not metabolised in animals and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although soon after administration the drug distributes widely in the body, this transient state is rapidly followed by a nonsaturable redistribution to skeletal tissues. Oral bioavailability is about 0.9 to 1.8%, and food markedly inhibits oral absorption. Removal of the drug from bone reflects the underlying rate of turnover of the skeleton. Renal clearance appears to involve both glomerular filtration and a specialised secretory pathway. Clinically, the pharmacokinetics of alendronate have been characterised almost exclusively based on urinary excretion data because of the extremely low concentrations achieved after oral administration. After intravenous administration of radiolabelled alendronate to women, no metabolites of the drug were detectable and urinary excretion was the sole means of elimination. About 40 to 60% of the dose is retained for a long time in the body, presumably in the skeleton, with no evidence of saturation or influence of one intravenous dose on the pharmacokinetics of subsequent doses. The oral bioavailability of alendronate in the fasted state is about 0.7%, with no significant difference between men and women. Absorption and disposition appear independent of dose. Food substantially reduces the bioavailability of oral alendronate; otherwise, no substantive drug interactions have been identified. The pharmacokinetic properties of alendronate are evident pharmacodynamically. Alendronate treatment results in an early and dose-dependent inhibition of skeletal resorption, which can be followed clinically with biochemical markers, and which ultimately reaches a plateau and is slowly reversible upon discontinuation of the drug. These findings reflect the uptake of the drug into bone, where it exerts its pharmacological activity, and a time course that results from the long residence time in the skeleton. The net result is that alendronate corrects the underlying imbalance in skeletal turnover characteristic of several disease states. In women with postmenopausal osteoporosis, for example, alendronate treatment results in increases in bone mass and a reduction in fracture incidence, including at the hip.