PGC-1 coactivators and skeletal muscle adaptations in health and disease

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Skeletal muscle adapts to physiological demands by altering a number of programs of gene expression, including those driving mitochondrial biogenesis, angiogenesis, and fiber composition. Recently, the PGC-1 transcriptional coactivators have emerged as key players in the regulation of these adaptations. Many signaling cascades important in muscle physiology impinge directly on PGC-1 expression or activity. In turn, the PGC-1s powerfully activate many of the programs of muscle adaptation. These findings have implications for our understanding of muscle responses to physiological conditions like exercise, as well as in pathological conditions such as cachexia, dystrophy, and peripheral vascular disease.

Introduction

Muscle converts chemical energy into physical work. The tasks demanded of muscle vary widely, ranging from rapid lifting of heavy weights to pumping blood without fault for decades. Moreover, these tasks change over time. To accommodate these changing conditions, muscle is both diverse in composition and highly plastic: the makeup and function of muscle can adapt to external factors like activity or hormonal exposure. This is true in both health and disease. Endurance exercise, for example, renders muscle more oxidative and resistant to fatigue. Conversely, disuse and systemic catabolic diseases lead to atrophy, with profound loss of muscle function. Understanding the molecular pathways underlying this plasticity is therefore of great interest.

Changes in metabolic programs are at the core of muscle plasticity. Great inroads have been made over the past decade into understanding the molecular pathways that drive these changes. The PGC-1 transcriptional coactivators, in particular, have emerged as an area of great interest in muscle bioenergetics because these proteins are dominant regulators of oxidative metabolism in many tissues. PGC-1α and PGC-1β powerfully regulate broad and comprehensive genetic programs, including the activation of fatty acid oxidation, oxidative phosphorylation, and numerous attendant activities needed to maintain functional mitochondria. This review will focus on the role of PGC-1 coactivators in muscle metabolism and plasticity (Figure 1).

Section snippets

Muscle composition

Skeletal muscle gains much of its heterogeneity during development. Muscle is composed of thousands of fibers, each of which is a syncytium of hundreds of cells stretching from one tendon to another. The tasks faced by groups of fibers or muscles range from continuous, low-level activities such as gravitational tasks (maintenance of posture) to sudden bursts of intense activity. To achieve such varied functions, fibers with different bioenergetic and biophysical properties exist [1, 2].

There

Muscle plasticity

Even though the baseline fiber-type composition of muscle is largely determined during development, adult muscle retains the capacity for substantial plasticity [1, 2]. Physical activity, or lack thereof, has particularly profound effects. Endurance training induces expansion of the mitochondrial compartment, significant angiogenesis, and a fast-to-slow fiber-type switch. This leads to improved endurance performance and resistance to fatigue, to the benefit of, for example, marathon runners.

The PGC-1 coactivators

Coactivators are proteins that dock on transcription factors and alter chromatin structure and the transcription machinery to stimulate gene expression. Most transcription factors probably bind to one or more coactivators to initiate transcription. Recently, coactivators have emerged as potent regulatory targets of physiological stimuli and hormones [8]. PGC-1α is the best-studied example of such a regulated coactivators [9]. PGC-1α was first identified as a cold-inducible PPAR-γ-binding

PGC-1s and oxidative metabolism

The PGC-1 coactivators have a variety of biological activities in different tissues, including muscle, and most of these activities are linked to oxidative metabolism. Both PGC-1α and PGC-1β are expressed at high levels in oxidative tissues such as the heart, brain, kidney, and muscle [20, 21]. When expressed ectopically, PGC-1α and PGC-1β induce mitochondrial biogenesis and increase cellular respiration in cell culture. PGC-1α −/− and PGC-1β −/− animals have abnormal skeletal and cardiac

PGC-1s and fiber types

In most of their tissue-specific roles, the PGC-1 coactivators increase a core program of mitochondrial biogenesis and respiration, as well as ancillary programs that go along with increased respiration in each tissue [9]. The expression of PGC-1α in white fat cells, for example, also gives them many of the properties of brown fat cells, including increased mitochondrial biogenesis and expression of UCP-1. In the liver, fasting induces PGC-1α, leading to gluconeogenesis and β-oxidation of fatty

PGC-1α and exercise

Endurance training induces mitochondrial biogenesis and a fast-to-slow fiber-type switch in skeletal muscle. Both PGC-1α and PGC-1β are more highly expressed in oxidative fibers [28, 29], and PGC-1α is preferentially expressed in type I-rich and type IIA-rich muscle beds like the soleus or deep gastrocnemius [28]. PGC-1α expression in human and rodent skeletal muscle is strongly induced by exercise (e.g. [40, 41, 42]), while PGC-1β expression appears unaffected. These observations, combined

PGC-1α and angiogenesis

Peripheral vascular disease is a leading cause of morbidity and the most common cause of limb amputation in the industrialized world. Chronic ischemia can have profound effects on muscle makeup. Because oxidative phosphorylation is by far the most efficient way to produce ATP, the robust output of ATP in muscle vitally depends on the efficient delivery of both oxygen and nutrients. Angiogenesis is therefore a crucial homeostatic response to chronic ischemia. Angiogenesis is a complex process

PGC-1α and disease

The large mass of proteins that make up the myofibrillar apparatus of skeletal muscle is a crucial reservoir for amino acids in the body. This reservoir can be tapped for energy needs in times of want, such as prolonged food deprivation, or in various pathologic conditions, such as cancer, sepsis, and renal and heart failure. Whereas protein breakdown is normal in response to prolonged fasting, wasting and cachexia associated with chronic disease can be debilitating. Indeed, skeletal muscle

Future directions

Many unanswered questions clearly require attention. Although many pathways can impinge on PGC-1α expression or activity, which of these operate in skeletal muscle in response to external cues is still unclear. For example, how deprivation of oxygen and nutrients induces PGC-1α, and precisely what pathways induce PGC-1α during exercise, remains only partly understood. How the PGC-1s integrate these multiple incoming signals is also in need of further study. For example, lack of oxygen/nutrients

Conflict of interest

The author has no conflict of interests.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Many important contributions were unfortunately not covered because of space limitations. Dr. Stew Lecker provided critical reading of the manuscript.

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