This review is divided into two parts, the first dealing with the cell and molecular biology of muscle in terms of growth and wasting and the second being an account of current knowledge of physiological mechanisms involved in the alteration of size of the human muscle mass. Wherever possible, attempts have been made to interrelate the information in each part and to provide the most likely explanation for phenomena that are currently only partially understood. The review should be of interest to cell and molecular biologists who know little of human muscle physiology and to physicians, physiotherapists, and kinesiologists who may be familiar with the gross behavior of human muscle but wish to understand more about the underlying mechanisms of change.

A hypothesis is presented based on a coalescence of anthropological estimations of Homo sapiens' phenotypes in the Late Paleolithic era 10,000 years ago, with Darwinian natural selection synergized with Neel's idea of the so-called thrifty gene. It is proposed that humans inherited genes that were evolved to support a physically active lifestyle. It is further postulated that physical inactivity in sedentary societies directly contributes to multiple chronic health disorders. Therefore, it is imperative to identify the underlying genetic and cellular/biochemical bases of why sedentary living produces chronic health conditions. This will allow society to improve its ability to effect beneficial lifestyle changes and hence improve the overall quality of living. To win the war against physical inactivity and the myriad of chronic health conditions produced because of physical inactivity, a multifactorial approach is needed, which includes successful preventive medicine, drug development, optimal target selection, and efficacious clinical therapy. All of these approaches require a thorough understanding of fundamental biology and how the dysregulated molecular circuitry caused by physical inactivity produces clinically overt disease. The purpose of this review is to summarize the vast armamentarium at our disposal in the form of the extensive scientific basis underlying how physical inactivity affects at least 20 of the most deadly chronic disorders. We hope that this information will provide readers with a starting point for developing additional strategies of their own in the ongoing war against inactivity-induced chronic health conditions.

Increasing the mechanical load on skeletal muscle results in increased expression of insulin-like growth factor I (IGF-I), which is thought to be a critical step in the induction of muscle hypertrophy. To determine the role of the IGF-I receptor in load-induced skeletal muscle hypertrophy, we utilized a transgenic mouse model (MKR) that expresses a dominant negative IGF-I receptor specifically in skeletal muscle. Skeletal muscle hypertrophy was induced in the plantaris muscle using the functional overload (FO) model, a model which has previously been shown to induce significant elevations of IGF-I expression in skeletal muscle. Adult male wild-type (WT) and MKR mice were subjected to 0, 7 or 35 days of FO. In control or unchallenged animals, the plantaris mass was 11% greater in WT compared to the MKR mice (P < 0.05). After 7 days of FO, plantaris mass increased significantly by 26% and 62% in WT and MKR mice, respectively (P < 0.05). After 35 days of FO, WT and MKR mice demonstrated significant increases of 100% and 122%, respectively, in plantaris mass (P < 0.05). Further, at no time point was the degree of hypertrophy significantly different between the WT and MKR mice. Previous research suggests that IGF-I induces muscle growth through activation of the Akt-mTOR signalling pathway; therefore, we measured the phosphorylation status of Akt and p70 s6k in the WT and MKR mice after 7 days of FO. Significant increases of ∼100% and ∼200% in Akt (Ser-473) and p70 s6k (Thr-389) phosphorylation were measured in overloaded plantaris from both WT and MKR mice, respectively. Moreover, no differences were detected between the WT and MKR mice. These data suggest that increased mechanical load can induce muscle hypertrophy and activate the Akt and p70 s6k independent of a functioning IGF-I receptor.

The current human genome was moulded and refined through generations of time. We propose that the basic framework for physiologic gene regulation was selected during an era of obligatory physical activity, as the survival of our Late Palaeolithic (50 000–10 000 BC) ancestors depended on hunting and gathering. A sedentary lifestyle in such an environment probably meant elimination of that individual organism. The phenotype of the present day Homo sapiens genome is much different from that of our ancient ancestors, primarily as a consequence of expressing evolutionarily programmed Late Palaeolithic genes in an environment that is predominantly sedentary. In this sense, our current genome is maladapted, resulting in abnormal gene expression, which in turn frequently manifests itself as clinically overt disease. We speculate that some of these genes still play a role in survival by causing premature death from chronic diseases produced by physical inactivity. We also contend that the current scientific evidence supports the notion that disruptions in cellular homeostasis are diminished in magnitude in physically active individuals compared with sedentary individuals due to the natural selection of gene expression that supports the physically active lifestyle displayed by our ancestors. We speculate that genes evolved with the expectation of requiring a certain threshold of physical activity for normal physiologic gene expression, and thus habitual exercise in sedentary cultures restores perturbed homeostatic mechanisms towards the normal physiological range of the Palaeolithic Homo sapiens. This hypothesis allows us to ask the question of whether normal physiological values change as a result of becoming sedentary. In summary, in sedentary cultures, daily physical activity normalizes gene expression towards patterns established to maintain the survival in the Late Palaeolithic era.

The purpose of this review is to present current understanding of cellular and molecular regulation of fibre type expression in skeletal muscle. Published literature seems to conclusively suggest that muscle fibre type expression is regulated by multiple signalling pathways and transcription factors rather than a single 'master' switch or signalling pathway. While the current nomenclature for fibre types is convenient for communication, based upon the evolution of this nomenclature, the prediction that fibre type classifications may change in the future to incorporate post-genomic information is made. It is predicted that future fibre type classifications could be based upon the contractile-activity-induced changes in a common regulatory factor(s) within a subpopulation of genes whose expressions are altered to modify and maintain the new muscle fibre phenotype.

There are many known growth factors/cytokines that induce skeletal muscle satellite cell proliferation. Currently, the signaling mechanisms in which these growth factors/cytokines activate satellite cell proliferation are not completely understood. Here, we sought to determine signaling mechanisms by which leukemia inhibitory factor (LIF) induces satellite cell proliferation in culture. First, we confirmed that LIF induces proliferation of C2C12 immortalized myoblasts and cultured primary rat satellite cells. In addition, we also found that this increase in proliferation can be inhibited by incubation of the cells in tyrphostin AG 490, a specific inhibitor of Janus-activated kinase (JAK) 2 activity. Furthermore, we also found that incubation of the cells at various time points with LIF (10 ng/ml) induces a significant, transient increase in JAK2 phosphorylation, signal transducers and activators of transcription (STAT3) phosphorylation, and STAT3 transcriptional activity. Increases in the STAT3-sensitive endogenous SOC3 protein followed these transient increases in STAT3 activation. In addition, AG 490 inhibited the increase in STAT3 phosphorylation. Finally, LIF did not change the phosphorylation status of extracellular signal-regulated protein kinase (ERK)1/2 or affect the phosphorylation status of Akt/protein kinase B. However, LY-294002, an inhibitor of phosphoinositide 3-kinase, blocked LIF-induced proliferation of satellite cells. These data suggest that LIF induces satellite cell proliferation by activation of the JAK2-STAT3 signaling pathway, suggesting that this may be an important pathway in muscle growth and/or hypertrophy.

To determine whether changes in glycogen synthase kinase-3beta (GSK-3beta) phosphorylation contribute to muscle hypertrophy, we delineated the effects of GSK-3beta activity on C(2)C(12) myotube size. We also examined possible insulin-like growth factor I (IGF-I) signaling of NFAT (nuclear factors of activated T cells)-inducible gene activity and possible modulation of NFAT activation by GSK-3beta. Application of IGF-I (250 ng/ml) or LiCl (10 mM) alone (i.e., both inhibit GSK-3beta activity) increased the area of C(2)C(12) myotubes by 80 and 85%, respectively. The application of IGF-I (250 ng/ml) elevated GSK-3beta phosphorylation and reduced GSK-3beta kinase activity by approximately 800% and approximately 25%, respectively. LY-294002 (100 microM) and wortmannin (150 microM), specific inhibitors of phosphatidylinositol 3'-kinase, attenuated IGF-I-induced GSK-3beta phosphorylation by 67 and 92%, respectively. IGF-I suppressed the kinase activity of GSK-3beta. IGF-I (250 ng/ml), but not LiCl (10 mM), induced an increase in NFAT-activated luciferase reporter activity. Cotransfection of a constitutively active GSK-3beta (cGSK-3beta) inhibited the induction by IGF-I of NFAT-inducible reporter activity. LiCl, which inhibits GSK-3beta, removed the block by cGSK-3beta on IGF-I-inducible NFAT-responsive reporter gene activity. These data suggest that the IGF-I-induced increase in skeletal myotube size is signaled, in part, through the inhibition of GSK-3beta.

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