Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways.

Myostatin, a member of the transforming growth factor-ß superfamily, is a potent negative regulator of skeletal muscle growth and is conserved in many species, from rodents to humans. Myostatin inactivation can induce skeletal muscle hypertrophy, while its overexpression or systemic administration causes muscle atrophy. As it represents a potential target for stimulating muscle growth and/or preventing muscle wasting, myostatin regulation and functions in the control of muscle mass have been extensively studied. A wealth of data strongly suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression. Moreover, myostatin plays a central role in integrating/mediating anabolic and catabolic responses. Myostatin negatively regulates the activity of the Akt pathway, which promotes protein synthesis, and increases the activity of the ubiquitin-proteasome system to induce atrophy. Several new studies have brought new information on how myostatin may affect both ribosomal biogenesis and translation efficiency of specific mRNA subclasses. In addition, although myostatin has been identified as a modulator of the major catabolic pathways, including the ubiquitin-proteasome and the autophagy-lysosome systems, the underlying mechanisms are only partially understood. The goal of this review is to highlight outstanding questions about myostatin-mediated regulation of the anabolic and catabolic signaling pathways in skeletal muscle. Particular emphasis has been placed on (1) the cross-regulation between myostatin, the growth-promoting pathways and the proteolytic systems; (2) how myostatin inhibition leads to muscle hypertrophy; and (3) the regulation of translation by myostatin.

High lipolytic activity and dyslipidemia in a spontaneous hypertensive/NIH corpulent (SHR/N-cp) rat: a genetic model of obesity and type 2 diabetes mellitus.

In order to better understand the link between obesity and type 2 diabetes, lipolysis and its adrenergic regulation was investigated in various adipose depots of obese adult females SHR/N-cp rats. Serum insulin, glucose, free fatty acids (FFA), triglycerides (TG) and glycerol were measured. Adipocytes were isolated from subcutaneous (SC), parametrial (PM) and retroperitoneal (RP) fat pads. Total cell number and size, basal lipolysis or stimulated by norepinephrine (NE) and BRL 37344 were measured in each depot. Obese rats were hyperinsulinemic and hyperglycemic, suggesting high insulin resistance. They presented a marked dyslipidemia, attested by increased serum FFA and TG levels. High serum glycerol levels also suggest a strong lipolytic rate. Obese rats showed an excessive development of all fat pads although a more pronounced effect was observed in the SC one. The cellularity of this depot was increased 8 fold when compared to lean rats, but these fat cells were only 1.5 to 2-fold larger. SC adipocytes showed a marked increase in their basal lipolytic activity but a lack of change in responsiveness to NE or BRL 37344. The association between high basal lipolysis and increased cellularity yields to a marked adipose cell lipolytic rate, especially from the SC region. SHR/N-cp rats were characterized by a hyperplasic type of obesity with an excessive development of the SC depot. The dyslipidemia, attested by an altered serum lipid profile could be attributed to excessive lipolysis that contributes to increased FFA levels, and to early development of insulin resistance through a lipotoxicity effect.

Alta actividad lipolítica y dislipidemia en la rata SHR/N-cp: módulo genético de obesidad y diabetes mellitus tipo 2 / High lipolytic activity and dyslipidemia in a Spontaneous Hypertensive/NIH Corpulent (SHR/N-cp) rat: a genetic model of obesity and type 2 diabetes mellitus

In order to better understand the link between obesity and type 2 diabetes, lipolysisand its adrenergic regulation was investigated in various adipose depots of obeseadult females SHR/N-cp rats. Serum insulin, glucose, free fatty acids (FFA), triglycerides(TG) and glycerol were measured. Adipocytes were isolated from subcutaneous(SC), parametrial (PM) and retroperitoneal (RP) fat pads. Total cell numberand size, basal lipolysis or stimulated by norepinephrine (NE) and BRL 37344 weremeasured in each depot. Obese rats were hyperinsulinemic and hyperglycemic, suggestinghigh insulin resistance. They presented a marked dyslipidemia, attested byincreased serum FFA and TG levels. High serum glycerol levels also suggest a stronglipolytic rate. Obese rats showed an excessive development of all fat pads although amore pronounced effect was observed in the SC one. The cellularity of this depot wasincreased 8 fold when compared to lean rats, but these fat cells were only 1.5 to2-fold larger. SC adipocytes showed a marked increase in their basal lipolytic activitybut a lack of change in responsiveness to NE or BRL 37344. The associationbetween high basal lipolysis and increased cellularity yields to a marked adipose celllipolytic rate, especially from the SC region. SHR/N-cp rats were characterized bya hyperplasic type of obesity with an excessive development of the SC depot. Thedyslipidemia, attested by an altered serum lipid profile could be attributed to excessivelipolysis that contributes to increased FFA levels, and to early development ofinsulin resistance through a lipotoxicity effect(AU)