TGFb and BMP signaling in skeletal muscle: potential significance for muscle-related disease Roberta Sartori 1, 2 , Paul Gregorevic 3 , and Marco Sandri 1, 2, 4 1 Dulbecco Telethon Institute, Venetian Institute of Molecular Medicine, 35129 Padova, Italy 2 Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy 3 Division of Cell Signaling and Metabolism, Baker IDI Heart and Diabetes Institute, Melbourne 3004, Australia 4 Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy The transforming growth factor beta (TGFb) superfamily comprises a large number of secreted proteins that regulate various fundamental biological processes un- derlying embryonic development and the postnatal reg- ulation of many cell types and organs. Sequence similarities define two ligand subfamilies: the TGFb/ activin subfamily and the bone morphogenetic protein (BMP) subfamily. The discovery that myostatin, a mem- ber of the TGFb/activin subfamily, negatively controls muscle mass attracted attention to this pathway. How- ever, recent findings of a positive role for BMP-mediated signaling in muscle have challenged the model of how the TGFb network regulates skeletal muscle phenotype. This review illustrates how this complex network inte- grates crosstalk among members of the TGFb superfam- ily and downstream signaling elements to regulate muscle in health and disease. The control of skeletal muscle mass: hypertrophy versus atrophy Skeletal muscle is a highly adaptive tissue, capable of altering muscle fiber size, functional capacity, and metab- olism in response to physiological stimuli. However, path- ological conditions can compromise the mechanisms that regulate muscle attributes, resulting in loss of muscle mass, functional impairment, and compromised metabo- lism. During development and in early postnatal life, the growth of skeletal muscle, like the mass of any other tissue, is influenced primarily by cellular turnover and secondarily by protein synthesis [1]. By contrast, recent data strongly support the concept that, in adulthood, reg- ulation of muscle mass and fiber size is determined by a complex integration of signaling cascades that collectively affect protein turnover, or the balance between relative rates of protein synthesis and degradation [2]. Growth of adult musculature is achieved primarily via increases in myofiber size – a process termed hypertrophy – that occur when enhancement of protein synthesis exceeds rates of protein degradation. The insulin-like growth factor 1 (IGF1)–phosphoinositide 3-kinase (PI3K)–Akt/protein kinase B (PKB)–mammalian target of rapamycin (mTOR) signaling pathway is considered the key controller of pro- tein synthesis in muscle, providing the means for potent control of S6, a ribosomal protein, and factor 4E-binding protein 1 (4EBP1), an inhibitor of the ribosomal eukaryotic translation initiator factor 4E (eIF4E) [3]. Conversely, loss of muscle mass typically involves atrophy of myofibers due to a net loss of proteins, organelles, and cytoplasm. Acute muscle atrophy, as observed in many pathological condi- tions, occurs due to hyperactivation of the main cellular degradation pathways, including the ubiquitin–protea- some and the autophagy–lysosome systems [4]. The acti- vation of these catabolic pathways requires upregulation of a program of atrophy-related genes, or atrogenes [5]. Expression of atrogenes is controlled by specific transcrip- tion factors including forkhead box O3 (FoxO3) [6,7], which is negatively regulated by Akt. Within this process, FoxO transcription factors strongly regulate transcription of the two best-characterized and most-induced muscle-specific atrophy-related ubiquitin ligases, atrogin1 (also known as MAFbx or Fbxo32) and MuRF1 (also called Trim63). These two E3 ubiquitin ligases catalyze the rate-limiting reaction in the ubiquitination process. Therefore, increasing the expression of these two enzymes enhances proteasome- dependent breakdown of target proteins. Other atrophy- related genes that encode proteins critical for the activity of the autophagy–lysosome system are discussed in Box 1 [4]. Excessive protein degradation in skeletal muscle that results in widespread muscle wasting (cachexia) is highly detrimental for the maintenance of muscle function and utilization of the body’s metabolic resources, with significant consequences in risk of increased morbidity and mortality. For instance, prominent atrophy of the intercostal and diaphragm musculature can significantly impair ventilato- ry function and result in respiratory failure, whereas atro- phy of the appendicular muscles can rob individuals of independent mobility. Individuals who become frail as a consequence of muscle atrophy frequently also exhibit re- duced tolerance to therapeutic interventions that may be prescribed to combat the primary illness (e.g., cancer thera- pies). Thus, maintenance of functional musculature is a leading factor in maintaining a healthy and independent Review 1043-2760/ ß 2014 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tem.2014.06.002 Corresponding author: Sandri, M. (marco.sandri@unipd.it). 464 Trends in Endocrinology and Metabolism, September 2014, Vol. 25, No. 9